U.S. patent number 10,272,048 [Application Number 15/267,156] was granted by the patent office on 2019-04-30 for delayed release drug formulation.
This patent grant is currently assigned to Tillotts Pharma AG. The grantee listed for this patent is Tillotts Pharma AG. Invention is credited to Abdul Waseh Basit, Roberto Carlos Bravo Gonzalez, Thomas Buser, Ana Cristina Freire, Felipe Jose Oliveira Varum.
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United States Patent |
10,272,048 |
Oliveira Varum , et
al. |
April 30, 2019 |
Delayed release drug formulation
Abstract
In a delayed release formulation comprising a core containing a
drug and a delayed release coating for providing intestinal
release, release of the drug in the colon is accelerated by
including an isolation layer between the core and the delayed
release coating. The delayed release coating comprises an inner
layer and an outer layer. The outer layer comprises a pH
dependently soluble polymeric material which has a pH threshold at
about pH 5 or above. The inner layer comprises a soluble polymeric
material which is soluble in intestinal fluid or gastrointestinal
fluid, said soluble polymeric material being selected from the
group consisting of a polycarboxylic acid polymer that is at least
partially neutralized, and a non-ionic polymer, provided that,
where said soluble polymeric material is a non-ionic polymer, said
inner layer comprises at least one additive selected from a buffer
agent and a base.
Inventors: |
Oliveira Varum; Felipe Jose
(Basel, CH), Bravo Gonzalez; Roberto Carlos
(Binningen, CH), Buser; Thomas (Nuglar,
CH), Basit; Abdul Waseh (Harrow, GB),
Freire; Ana Cristina (Northampton, GB) |
Applicant: |
Name |
City |
State |
Country |
Type |
Tillotts Pharma AG |
Rheinfelden |
N/A |
CH |
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Assignee: |
Tillotts Pharma AG
(Rheinfelden, CH)
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Family
ID: |
46025554 |
Appl.
No.: |
15/267,156 |
Filed: |
September 16, 2016 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20170035698 A1 |
Feb 9, 2017 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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14066054 |
Oct 29, 2013 |
9814681 |
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PCT/EP2013/058921 |
Apr 29, 2013 |
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PCT/EP2013/058923 |
Apr 29, 2013 |
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61640217 |
Apr 30, 2012 |
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Foreign Application Priority Data
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Apr 30, 2012 [EP] |
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12166110 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/606 (20130101); A61K 47/32 (20130101); A61P
1/10 (20180101); A61K 9/2866 (20130101); A61K
9/286 (20130101); A61K 9/2886 (20130101); A61K
9/2846 (20130101); A61P 31/00 (20180101); A61K
9/284 (20130101); A61K 31/616 (20130101); A61K
9/2054 (20130101); A61P 1/04 (20180101); A61K
9/288 (20130101); A61K 9/2013 (20130101); A61K
9/2893 (20130101); A61K 47/36 (20130101); A61K
47/38 (20130101); A61K 9/2853 (20130101); A61P
35/00 (20180101); A61P 1/12 (20180101); A61K
9/0053 (20130101); A61K 31/196 (20130101) |
Current International
Class: |
A61K
9/28 (20060101); A61K 31/196 (20060101); A61K
47/38 (20060101); A61K 31/606 (20060101); A61K
31/616 (20060101); A61K 47/36 (20060101); A61K
9/20 (20060101); A61K 47/32 (20060101); A61K
9/00 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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Feb 2011 |
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EP |
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0 502 032 |
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Sep 1992 |
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EP |
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2 367 002 |
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Mar 2002 |
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GB |
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WO 91/07949 |
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Jun 1991 |
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WO |
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WO 96/36321 |
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Nov 1996 |
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WO |
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WO 99/21536 |
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May 1999 |
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WO |
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WO 99/25325 |
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May 1999 |
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WO |
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WO 01/76562 |
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Oct 2001 |
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WO |
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WO 03/068196 |
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Aug 2003 |
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WO |
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WO 2004/052339 |
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Jun 2004 |
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WO |
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WO 2007/122374 |
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Nov 2007 |
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WO |
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WO 2008/135090 |
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Nov 2008 |
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WO |
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WO 2008/135090 |
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Nov 2008 |
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WO |
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2013/035081 |
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Mar 2013 |
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WO |
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Other References
Karrout "innovative Drug Delivery System for colon Targeting" 2008.
cited by examiner .
International Search Report and Written Opinion dated Jul. 11, 2013
in PCT/EP2013/058921. cited by applicant .
International Search Report and Written Opinion dated Jul. 10, 2013
in PCT/EP2013/058923. cited by applicant .
Masataka Katsuma, et al., "Studies on lactulose formulations for
colon-specific drug delivery" International Journal of
Pharmaceutics, vol. 249, No. 1-2, XP055033720, Dec. 1, 2002, pp.
33-43. cited by applicant .
Frederick Esseku, et al., "Bacteria and pH-Sensitive
Polysaccharide-Polymer Films for Colon Targeted Delivery" Critical
Reviews in Therapeutic Drug Carrier Systems, vol. 28, No. 5,
XP009161434, 2011, pp. 395-445. cited by applicant .
Snezana Milojevic, et al., "Amylose as a coating for drug delivery
to the colon: Preparation and in vitro evaluation using
5-aminosalicylic acid pellets" Journal of Controlled Release, vol.
38, 1996, pp. 75-84. cited by applicant .
A. Akhgari, et al., "Permeability and swelling studies on free
films containing inulin in combination with different
polymethacrylates aimed for colonic drug delivery" European Journal
of Pharmaceutical Sciences, vol. 28, Mar. 2006, pp. 307-314. cited
by applicant .
Heini Kari, "An investigation of combined pH- and
bacterially-triggered oral colon targeted drug delivery system"
Seminar Abstract, Sep. 2, 2009, 6 Pages. cited by applicant .
Fang Liu, et al., "A novel concept in enteric coating: A
double-coating system providing rapid drug release in the proximal
small intestine" Journal of Controlled Release, vol. 133, 2009, pp.
119-124. cited by applicant .
Fang Liu, et al., "SEM/EDX and confocal microscopy analysis of
novel and conventional enteric-coated systems" International
Journal of Pharmaceutics, vol. 369, 2009, pp. 72-78. cited by
applicant .
Fang Liu, et al., "A novel double-coating approach for improved pH-
triggered delivery to the ileo-colonic region of the
gastrointestinal tract" European Journal Pharmaceutics and
Biopharmaceutics, vol. 74, 2010, pp. 311-315. cited by
applicant.
|
Primary Examiner: Wax; Robert A
Assistant Examiner: Al-Awadi; Danah
Attorney, Agent or Firm: Oblon, McClelland, Maier &
Neustadt, L.L.P.
Parent Case Text
The present application is a divisional of U.S. application Ser.
No. 14/066,054 filed Oct. 29, 2013, pending, which is a
Continuation-in-part of PCT/EP2013/05891 filed Apr. 29, 2013, a
Continuation-in-part of PCT/EP2013/058923 filed Apr. 29, 2013, and
claims the benefit of U.S. application Ser. Nos. 61/640,217 filed
Apr. 30, 2012 and 61/640,217 filed Apr. 30, 2012.
Claims
The invention claimed is:
1. A method for preventing deceleration of drug release in the
intestine of a subject from a delayed release drug formulation for
oral administration to said subject after storage of said delayed
release drug formulation, wherein said delayed release drug
formulation comprises a core comprising a drug; and an outer
coating for providing intestinal release of said drug, said outer
coating comprising an outer layer and an inner layer, wherein the
outer layer comprises a pH dependently soluble polymeric material
which has a pH threshold at about pH 5 or above, and wherein the
inner layer comprises a soluble polymeric material which is soluble
in intestinal fluid or gastrointestinal fluid, said soluble
polymeric material being a polycarboxylic acid polymer that is at
least partially neutralized, with at least 90% of the carboxylic
acid groups of said polycarboxylic acid polymer being in the form
of carboxylate anions; said method comprising, providing an
isolation layer between said core and said inner layer.
2. The method of claim 1, wherein lag time in vitro in Krebs buffer
at pH 7.4 after 2 h at 0.1M HCl is increased after storage by no
more than 5%.
3. The method as claimed in claim 1, wherein lag time in vitro in
Krebs buffer at pH 7.4 after 2 h at 0.1M HCl is increased after
storage by no more than 10 minutes.
4. The method of claim 1, wherein said delayed release drug
formulation is stored in a closed high density polyethylene
container for at least 1 month at 40.degree. C./75% RH.
5. The method of claim 1, wherein said delayed release drug
formulation is stored in a closed high density polyethylene
container for at least 3 months at 25.degree. C./60% RH.
6. The method of claim 1, wherein said isolation layer comprises
hydroxypropyl methylcellulose.
7. The method of claim 1, wherein said outer layer comprises said
pH dependently soluble polymeric material in admixture with a
digestible polymeric material susceptible to attack by colonic
bacteria.
Description
The present invention relates to a delayed release formulation with
a core comprising a drug and a coating for providing delaying
release of the drug until the colon. In particular, it relates to
use of an isolation layer to accelerate initial release of the drug
once the intestine is reached.
The targeting of drugs to the intestine is well known and has been
known for over one hundred years. Commonly, the target of the drugs
is the small intestine although the colon can be utilised as a
means of achieving local therapy or systemic treatment. The
requirements for the coatings on the drugs are different depending
on the target site. In order to reach the colon, it is necessary
for the drugs to pass through the small intestine, and therefore it
is a requirement that a delayed release coating intended to release
the drug in the colon does not release the drug in the small
intestine.
Coated products for release in the small intestine commonly use
polymer coatings which dissolve or disintegrate in a pH dependent
manner. In the low pH environment of the stomach, the polymer
coating is insoluble. However, on reaching the small intestine, the
pH rises to 5 and above and the polymeric coating dissolves or
disintegrates. A commonly used coating is one containing ionisable
carboxylic groups. At higher pH levels, the carboxylic groups
ionize, allowing the polymer coatings to disintegrate or dissolve.
Common polymers of this type which are used include Eudragit.RTM. L
and Eudragit.RTM. S.
Various methods of improving the release in the small intestine by
ensuring an earlier release of the drug are known. US2008/0200482
is one of a number of references which discloses partially
neutralizing the carboxylic groups in order to reduce the pH at
which disintegration occurs. WO2008/135090 discloses a tablet with
an inner coat of partially neutralized material and an outer coat
with less or no neutralization. This is said to result in
disintegration at an earlier time point when transferred from the
stomach.
Release of drugs in the colon typically requires an alternative
approach. The colon is susceptible to a number of disease states,
including inflammatory bowel disease, irritable bowel syndrome,
constipation, diarrhoea, infection and carcinoma. In such
conditions, drug targeting to the colon would maximise the
therapeutic effectiveness of the treatment. The colon can also be
utilised as a portal for the entry of drugs into the systemic
circulation. Various formulations have been developed for colonic
drug delivery, including pro-drugs as well as formulated dosage
forms, with the latter being more popular since the concept once
proved can be applied to other drugs.
The higher bacterial population in the colon has also been
exploited in developing colonic drug delivery dosage forms through
the use, as carrier materials, of naturally occurring
polysaccharides that constitute substrates for the numerous enzymes
of the resident colonic bacteria. These materials are able to pass
through the upper gastrointestinal regions intact but are digested
upon entry into the colon. Those studied so far include amylose,
pectin, chitosan and galactomannan.
One major attraction of using polysaccharides in this bacterial
enzyme approach to colonic drug delivery is that materials used are
of food grade and so would be safe for use in humans. They are
usually applied as coatings or incorporated in the core material as
a matrix carrier, and their digestion on entry into the colon by
the colonic bacterial enzymes leads to the release of the drug
load. An example of such a formulation, which employs an amylose
coating, is disclosed in EP0343993A (BTG International
Limited).
EP0502032A (British Technology Group Ltd) teaches the use of an
outer coating comprising a film forming cellulose or acrylate
polymer material and amorphous amylose for a tablet comprising an
active compound. The polymer material used is a pH independent
release polymer material.
An article in Journal of Controlled Release (Milojevic et al; 38;
(1996); 75-84) reports the results of investigations concerning the
incorporation of a range of insoluble polymers into an amylose
coating in order to control amylose swelling. A range of cellulose
and acrylate based co-polymers are assessed, and a commercially
available ethyl cellulose (Ethocel.RTM.) is found to control the
swelling most effectively. A pH dependent soluble coating of
Eudragit.RTM. L100 is employed but only in a multi-layer system
comprising a bioactive coated with an inner coating of amylose and
then an outer coating of Eudragit.RTM. L100.
A further amylose-based coating composition is disclosed in
WO99/21536A (BTG International Limited). The coating composition
comprises a mixture of amylose and a water insoluble pH independent
film-forming polymer which is formed from a water-insoluble
cellulosic or acrylate polymer material.
WO99/25325A (BTG International Limited) also discloses a delayed
release coating comprising amylose and (preferably) ethyl cellulose
or alternatively an insoluble acrylate polymer. The coating
composition also includes a plasticiser and the method finds
particular application in the preparation of dosage forms
comprising active materials that are unstable at temperatures in
excess of 60.degree. C., as the composition is formed at lower
temperatures than this.
WO03/068196A (Alizyme Therapeutics Ltd) discloses a specific
delayed release coating for the bioactive prednisolone sodium
metasulphobenzoate comprising glassy amylose, ethyl cellulose and
dibutyl sebacate.
The use of polysaccharides other than amorphous amylose in a
delayed release coating is disclosed in GB2367002 (British Sugar
PLC). Examples include guar gum, karaya gum, gum tragacanth and
xanthan gum. Microparticles of these polysaccharides are dispersed
in a water-insoluble film-forming polymer matrix formed for example
from a cellulose derivative, an acrylic polymer or a lignin.
WO01/76562A (Tampereen Patenttitoimisto Oy) discloses a per oral
pharmaceutical formulation containing a drug and a chitosan (a
polysaccharide obtained from chitin) for controlling its release.
The drug and the chitosan are mixed into a homogeneous mechanical
powder mixture which is granulated and then optionally tableted.
The granulation may be performed with an enteric polymer (such as a
copolymer of methacrylic acid) or the granules may be provided with
a porous enteric coating.
WO2004/052339A (Salvona LLC) discloses a pH dependent drug release
system which is a free-flowing powder of solid hydrophobic
nano-spheres comprising a drug encapsulated in a pH-sensitive
micro-sphere. The nano-spheres are formed from the drug in
combination with a wax material, and the pH-sensitive micro-sphere
formed from a pH-sensitive polymer (such as a Eudragit.RTM.
polymer) in combination with a water-sensitive material such as a
polysaccharide.
An article in the European Journal of Pharmaceutical Sciences
(Akhgari et al; 28; March 2006; 307-314) reports the results of
investigations into the use of certain polymethacrylate polymers
to, inter alia, control the swelling of inulin. The
polymethacrylate polymers tested were Eudragit.RTM. RS;
Eudragit.RTM. RL; 1:1 mixtures of Eudragit.RTM. RS and
Eudragit.RTM. RL; Eudragit.RTM. FS; and 1:1 mixtures of
Eudragit.RTM. RS and Eudragit.RTM. S.
U.S. Pat. No. 5,422,121 (Rohm GmbH) discloses an oral dosage form
having a core containing at least one active ingredient enclosed
within a shell material which comprises a polysaccharide that
decomposes in the colon in admixture with a film-forming polymer.
The ratio by weight of polysaccharide to film forming polymer is
from 1:2 to 5:1, preferably from 1:1 to 4:1. Premature diffusion of
the active ingredient from the core can be suppressed using a
gastric resistant isolating layer. The reference exemplifies inter
alia tablets having an inner isolating layer of Eudragit.RTM. L30D
with an outer layer comprising Eudragit.RTM. L30D and guar gum
(Example 2).
WO96/36321A discloses an oral dosage form comprising a core
containing bisacodyl, and an enteric polymer coating for the core,
the coating comprising at least one inner coating layer and an
outer coating layer. The or each the inner coating layer is an
enteric polymer that begins to dissolve in an aqueous medium at a
pH from about 5 to about 6.3, and the outer coating layer is an
enteric polymer that begins to dissolve in an aqueous medium at a
pH from about 6.8 to about 7.2. The enteric polymer coating
materials for the inner layer(s) are selected from the group
consisting of cellulose acetate phthalate; cellulose acetate
trimellitate; hydroxypropyl methylcellulose phthalate;
hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate
phthalate; poly(methacrylic acid, methyl methacrylate) 1:1;
poly(methacrylic acid, ethyl acrylate) 1:1; and compatible mixtures
thereof.
An abstract entitled "An investigation of combined pH- and
bacterially-triggered oral colon targeted drug delivery system" by
Heini Kari of the Department of Pharmaceutical Technology in the
Faculty of Pharmacy at University of Helsinki dated 2 Sep. 2009
discloses tablet formulations having a heat treated
polysaccharide/Eudragit.RTM. S coating for colonic release and an
HPMC sub-coating. Very few details of the formulations are provided
in the abstract. For example, the identity of the polysaccharide,
the proportions of the polysaccharide and Eudragit.RTM. S in the
coating and the identity and proportions of any excipients are not
provided. However, it is disclosed that tablets with heat treated
coatings, and especially with HPMC sub-coatings, had "better" drug
release profiles than completely organic coatings in the
conventional dissolution tests in the presence of one enzyme. No
details of how or why the drug release profile is better are
provided although the author speculates that the reason may be
because of a more uniform coating structure in which polysaccharide
granules are not present.
In a paper entitled "A novel concept in enteric coating: A
double-coating system providing rapid drug release in the proximal
small intestine" by Liu et al (J. Cont. Rel. 133 (2009) 119-124),
it is disclosed that release of prednisolone from tablets having a
double coating system comprising an inner coat of partially
neutralised Eudragit.RTM. L 30 D-55 and organic acid, and an outer
coat of standard Eudragit.RTM. L 30 D-55 was accelerated in
conditions resembling the upper small intestine. The inner coat was
neutralised to pH 5.6 in the presence of 10% citric acid or adipic
acid. The tablets did not have an isolation layer.
In a paper entitled "SEM/EDX and confocal microscopy analysis of
novel and conventional enteric-coated systems" by Liu et al (Int.
J. Pharm. 369 (2009) 72-78), it is disclosed that prednisolone was
released more rapidly from tablets coated with an inner coat of
partially neutralised Eudragit.RTM. L 30 D-55 and organic acid, and
an outer coat of standard Eudragit.RTM. L 30 D-55, than from
tablets coated with Eudragit.RTM. L 30 D-55 alone with or without a
subcoat of HPMC. The double coated tablets did not have a subcoat
of HPMC although the authors of the paper observed that drug
release from the tablets having the single enteric coat with the
HPMC subcoat was faster than from the single enteric coated tablets
without the subcoat.
It is also reported in a paper entitled "A novel double-coating
approach for improved pH-triggered delivery to the ileo-colonic
region of the gastrointestinal tract" by Liu et al (Eur. J. Pharm.
Biopharm. 74 (2010) 311-315), that initial release in vitro (in
Krebs buffer (pH 7.4) after 2 h in 0.1 M HCl) of prednisolone was
faster from tablets coated with a coating system comprising an
inner layer of partially neutralised Eudragit S and buffer agent
and an outer layer of standard Eudragit S, than from tablets
without the inner layer. None of the tablets disclosed in this
paper had an isolation layer.
WO2007/122374A discloses a colonic drug delivery formulation in
which a mixture of a pH dependent film forming polymeric material
and a polysaccharide such as starch is used. Although it is known
that this formulation shows delayed release followed by a
relatively quick release of the drug, it would be preferred if the
drug release was even quicker in the colon, after the triggers are
initiated.
In accordance with a first aspect of the present invention, there
is provided an isolation layer for use in accelerating drug release
in the intestine of a subject from a delayed release drug
formulation for oral administration to said subject, said
formulation comprising: a core comprising said drug; said isolation
layer coating said core; and an outer coating for providing
intestinal release of said drug, said outer coating comprising an
outer layer and an inner layer, wherein said outer layer comprises
a pH dependently soluble polymeric material which has a pH
threshold at about pH 5 or above, and wherein the inner layer
comprises a soluble polymeric material which is soluble in
intestinal fluid or gastrointestinal fluid, said soluble polymeric
material being selected from the group consisting of a
polycarboxylic acid polymer that is at least partially neutralised,
and a non-ionic polymer, provided that, where said soluble
polymeric material is a non-ionic polymer, said inner layer
comprises at least one additive selected from a buffer agent and a
base.
The Inventors have discovered that the use of an isolation layer in
such formulations accelerates initial release of the drug once the
formulations are exposed to pH conditions found in the colon. This
result was entirely unexpected. The Inventors introduced the
isolation for the purpose of preventing erosion at the edges of the
tablets prior to coating. They fully expected the additional layer
to further delay release in line with conventional wisdom. However,
they were surprised to observe that, rather than delay initial
release, the isolation layer actually accelerated initial once the
coated tablets were exposed to colonic pH. The Inventors are not
aware of any literature which could have predicted such a
result.
The isolation layer also improves the stability of the formulations
during storage by preventing deceleration of initial release over
time.
In preferred embodiments, the isolation layer comprises a
film-forming non-ionic polymer, such as HPMC or PVA, and typically
has a thickness from about 1 mg polymer/cm.sup.2 to about 5 mg
polymer/cm.sup.2.
In some preferred embodiments, the pH dependently soluble polymeric
material is the sole film forming polymer in the outer layer.
However, in other preferred embodiments, the outer layer has a
mixture of a digestible (or "first") polymeric material susceptible
to attack by colonic bacteria, e.g. a polysaccharide, and the pH
dependently soluble (or "second") polymeric material.
The soluble (or "third") polymeric material that is soluble in
intestinal fluid or gastrointestinal fluid is typically a partially
or fully neutralised polycarboxylic acid polymer.
In these embodiments, the pH dependently soluble (or second)
polymer material is typically a polycarboxylic acid polymer of the
same type as the polymer of the inner layer but either
non-neutralised or partially neutralised to a lower extent than the
soluble (or third) polymeric material.
Formulations according to embodiments of the present invention have
superior colonic-release properties over comparative coatings
designed for site-specific release in the colon. In this
connection, drug release from formulations according to embodiments
of the present invention appears to be accelerated in the colon
when compared to comparative colonic release formulations. The
Inventors are confident that other formulations within the scope of
the invention should also have superior release properties over
comparative coatings designed for site-specific release in the
small intestine, and proximal small intestine in particular.
Broadly speaking, the region of the intestine in which initial
release occurs can be controlled by the choice of pH dependently
soluble polymeric material.
Without wishing to be bound by any particular theory, the Inventors
believe that, once intestinal fluid or gastrointestinal fluid
penetrates the outer layer, the inner layer begins to dissolve
before the outer layer to form a fluid region between the core and
the outer layer. The fluid region not only facilitates dissolution
and/or disintegration of the outer layer from the inside, but also
softens and begins to break up the core so that, when the outer
layer degrades, the drug is released from the core more
quickly.
In some preferred embodiments, the further acceleration provided by
the isolation layer is very likely due to the barrier effect
between an acidic core (e.g. a core containing 5ASA) and an
alkaline inner layer. In these embodiments, the Inventors believe
that the isolation layer prevents or limits the effect of the
acidic drug on the alkaline inner layer, not compromising and/or
competing for the alkalinity which promotes the accelerated
dissolution of the outer layer.
It is preferred that the digestible (or first) polymeric material
comprises at least one polysaccharide selected from the group
consisting of starch; amylose; amylopectin; chitosan; chondroitin
sulphate; cyclodextrin; dextran; pullulan; carrageenan;
scleroglucan; chitin; curdulan and levan. It is particularly
preferred that the digestible (or first) polymeric material is
starch.
In preferred embodiments, the pH dependently soluble (or second)
polymeric material is an anionic polymeric material, and more
preferably an anionic copolymer of a (meth)acrylic acid and a
(meth)acrylic acid alkyl ester.
The soluble (or third) polymeric material of the inner layer is
preferably an anionic polymeric material and more preferably an at
least partially neutralised, preferably fully neutralised,
copolymer of a (meth)acrylic acid and a (meth)acrylic acid alkyl
ester.
In a preferred embodiment, the second polymeric material is the
same type of copolymer of a (meth)acrylic acid and a (meth)acrylic
acid alkyl ester as the third polymeric material prior to
neutralisation.
In a particularly favourable embodiment, the present invention
relates to a delayed release drug formulation comprising a core
comprising a drug, an isolation layer for the core and a delayed
release coating for the isolated core, the delayed release coating
comprising an outer layer and an inner layer, wherein the outer
layer comprises a mixture of starch and a copolymer of a
(meth)acrylic acid and a (meth)acrylic acid C.sub.1-4 alkyl ester;
and the inner layer comprises a fully neutralized copolymer of a
(meth)acrylic acid and a (meth)acrylic acid C.sub.1-4 alkyl
ester.
Some materials that are susceptible to attack by colonic bacteria,
e.g. amylose, swell when exposed to aqueous fluid, e.g.
gastrointestinal fluid. Such swelling is undesirable since it
results typically in premature release of the drug. The swelling is
controlled by the inclusion of a pH dependent material having a pH
threshold of pH 5 or above.
A further technical advantage of the present invention (compared,
for example, to the formulation disclosed in WO01/76562A) is that
substantially no drug is released for an extended period (that is,
whilst the coating is intact and is being dissolved/disintegrated),
following which the drug is released relatively quickly. This is in
contrast to homogeneous tablets from which the drug release profile
is gradual from the outset rather than delayed then pulsatile.
A yet further technical advantage of the present invention compared
to WO2007/122374A is accelerated release of the drug once the
formulation is exposed to the conditions of the colonic
environment.
Isolation Layer
The isolation layer typically accelerates initial release of the
drug in the intestine from the present formulation compared to an
equivalent formulation without the isolation layer.
By "accelerating release", the Inventors mean reducing the delay
before initial release of the drug once exposed to intestinal
conditions. This delay is referred to as the lag time or
T.sub.lag.
The present invention has particular application in accelerating
release in the colon. According to these embodiments of the present
invention, the lag time (T.sub.lag) in vitro in Krebs buffer at pH
7.4 after 2 h at 0.1M HCl is typically reduced by at least 10%,
preferably by at least 20%, more preferably by at least 30% and
most preferably by at least 40%. In absolute terms, the lag time
(T.sub.lag) in vitro in Krebs buffer at pH 7.4 after 2 h at 0.1M
HCl is typically reduced by at least 10 minutes, preferably by at
least 20 minutes, more preferably by at least 30 minutes, and most
preferably by at least 45 minutes.
In other embodiments, the isolation layer is for use in
accelerating drug release in the small intestine, and particularly
in the proximal small intestine, of the subject. According to these
embodiments of the present invention, the lag time (T.sub.lag) in
vitro in a buffered solution at an appropriate pH (e.g. pH 5.5 for
the proximal small intestine or pH 6.8 to 7.2 for the ileum) after
2 h at 0.1M HCl is typically similar to that indicated above at pH
7.4.
The polymeric material of the isolation layer is preferably present
in the isolation layer in a total amount from about 1 mg
polymer/cm.sup.2 to about 5 mg polymer/cm.sup.2, preferably from
about 2 mg polymer/cm.sup.2 to about 4 mg polymer/cm.sup.2, more
preferably from about 2.5 mg polymer/cm.sup.2 to about 3.5 mg
polymer/cm.sup.2, and most preferably of about 3 mg
polymer/cm.sup.2, as such coating amounts tend to provide optimum
improvement in acceleration of initial release.
The thickness of the isolation layer is typically from about 5
.mu.m to about 100 .mu.m, preferably from about 10 .mu.m to about
60 .mu.m, and most preferably from about 20 .mu.m to about 40
.mu.m. Such coating thicknesses typically provide optimum
improvement in acceleration of initial release.
By "thickness" of a layer or coating, the Inventors are referring
to the perpendicular dimension between the inner and outer surfaces
of the layer or coating in question. The values provided herein
regarding layer or coating thickness are a mean average of the
thickness measured at different points of a cross-section of the
coated dosage form, including at the edges where the layer or
coating is typically thinner.
The thickness of a layer or coating on an oral dosage form such as
a tablet, is generally measured by subjecting the cross section of
the dosage form to scanning electron microscopy (SEM) and then by
using the measurement software of the SEM instrument (i.e. Phenom
SEM measurement software) or any other measurement software like
MeasureIT from Olympus Soft Imaging Solutions GmbH. However, SEM
may not be specific enough in some cases, including in cases where
adjacent layers cannot be distinguished properly, or where the
typical margin of error in SEM (about 5 to 10%) is not acceptable.
In such cases, the thickness of the coating or layer to be
distinguished can be determined precisely using atomic force
microscopy (AFM) or terahertz pulsed spectroscopy and imaging
(TPI). A method of using TPI to measure the thickness of a layer in
a tablet is described in the Journal of Pharmacy and Pharmacology
(2007), 59: 209-223.
As indicated above, the isolation layer typically comprises at
least one non-ionic polymer. Suitable polymers include at least one
polymer selected from the group consisting of methylcellulose (MC);
hydroxypropyl cellulose (HPC); hydroxypropyl methylcellulose
(HPMC); poly(ethylene oxide)-graft-polyvinyl alcohol;
polyvinylpyrollidone (PVP); and polyvinyl alcohol (PVA).
In some embodiments, the isolation layer does not need to include a
plasticizer. However, in other embodiments, the isolation layer can
additionally comprise at least one plasticizer to provide better
film quality. Any suitable plasticizers may be used, including
triethyl citrate (TEC) and polyethylene glycol (PEG). The total
amount of plasticizer(s) in the layer is typically from about 5 wt
%) to about 50 wt %, e.g. from about 10 wt % to about 30 wt %. In
some embodiments, the total amount of plasticizer may be about 20
wt %.
In some preferred embodiments, the isolation layer comprises HPMC.
In other preferred embodiments, the isolation layer comprises
PVA.
The non-ionic polymer is typically present in the isolation layer
as the sole film-forming polymeric material.
Digestible (or First) Polymeric Material
The digestible (or first) polymeric material typically comprises a
polysaccharide, preferably containing a plurality of hexose units.
In a preferred embodiment, the polysaccharide is at least one
polysaccharide selected from the group consisting of starch;
amylose; amylopectin; chitosan; chondroitin sulphate; cyclodextrin;
dextran; pullulan; carrageenan; scleroglucan; chitin; curdulan and
levan. It is further preferred that the polysaccharide is starch,
amylose or amylopectin, most preferably starch.
The person skilled in the art is capable of determining whether a
polymeric material is susceptible to attack by colonic bacteria
using techniques comprising part of the common general knowledge.
For example, a pre-determined amount of a given material could be
exposed to an assay containing an enzyme from a bacterium found in
the colon and the change in weight of the material over time may be
measured.
The polysaccharide is preferably starch. Starches are usually
extracted from natural sources such as cereals; pulses; and tubers.
Suitable starches for use in the present invention are typically
food grade starches and include rice starch; wheat starch; corn (or
maize) starch; pea starch; potato starch; sweet potato starch;
tapioca starch; sorghum starch; sago starch; and arrow root starch.
The use of maize starch is exemplified below.
Starch is typically a mixture of two different polysaccharides,
namely amylose and amylopectin. Different starches may have
different proportions of these two polysaccharides. Most natural
(unmodified) maize starches have from about 20 wt %) to about 30 wt
% amylose with the remainder being at least substantially made up
of amylopectin. Starches suitable for use in the present invention
typically have at least 0.1 wt %, e.g. at least 10% or 15%,
preferably at least 35 wt %, amylose.
"High amylose" starches, i.e. starches having at least 50 wt %
amylose, are suitable. Particularly suitable starches have from
about 55 wt % to about 75 wt %, e.g. about 60 wt % or about 70 wt %
amylose. In particular, starches having from about 50 wt % to about
60 wt % amylose are also suitable,
Starches suitable for use in the present invention may have up to
100% amylopectin, more typically from about 0.1 wt % to about 99.9
wt % amylopectin. "Low amylose" starches, i.e. starches having no
more than 50 wt % amylose and at least 50 wt % amylopectin, e.g. up
to 75 wt % amylopectin and even as much as up to 99 wt %
amylopectin, are still suitable. The starch may be, for example,
unmodified waxy corn starch. This typically comprises about 100%
amylopectin.
Preferred starches have no more than 50 wt % amylopectin. As
indicated above, particularly suitable starches are "high amylose"
starches which have from about 25 wt % to about 45 wt %
amylopectin, e.g. about 30 wt % or about 40 wt % amylopectin. In
particular, starches having from about 40 wt % to about 50 wt %
amylopectin are also suitable.
The person skilled in the art is capable of determining the
relative proportions of amylose and amylopectin in any given
starch. For example, near-infrared ("NIR") spectroscopy could be
used to determine the amylose and amylopectin content of a starch
using calibration curves obtained by NIR using laboratory-produced
mixtures of known amounts of these two components. Further, starch
could be hydrolysed to glucose using amyloglucosidase. A series of
phosphorylation and oxidation reactions catalysed by enzymes result
in the formation of reduced nicotinamide adenine dinucleotide
phosphate ("NADPH"). The quantity of NADPH formed is stoichiometric
with the original glucose content. Suitable test kits for this
procedure are available (e.g., R-Biopharm GmbH, Germany). Another
method that could be used involves subjecting the coating to
digestion by bacterial enzymes, e.g. .alpha.-amylase, to produce
short chain fatty acids ("SCFA") which can be quantified by
gas-liquid chromatography using a capillary column.
Preferred starches have amylose in its glassy form although amylose
in its amorphous form may also be used in conjunction with the
present invention.
Preferred starches are "off-the-shelf" starches, i.e. starches
which require no processing prior to use in the context of the
present invention. Examples of particularly suitable "high amylose"
starches include Hylon.TM. VII (National Starch, Germany),
Eurylon.TM. 6 (or VI) or Amylo NI-460 or Amylo N-400 (Roquette,
Lestrem, France), or Amylogel 03003 (Cargill, Minneapolis, USA) all
of which are examples of a maize starch having from about 50 wt %
to about 75 wt % amylose.
pH Dependently Soluble (or Second) Polymeric Material
The present invention involves the use of a pH dependently soluble
(or second) polymeric material that dissolves in a pH dependent
manner. The second material is a film forming polymer that is pH
sensitive, i.e. has a "pH threshold" which is the pH below which it
is insoluble in aqueous media and at or above which it is soluble
in aqueous media. Thus, the pH of the surrounding medium triggers
dissolution of the second polymeric material and none (or
essentially none) of the second polymeric material dissolves below
the pH threshold. Once the pH of the surrounding medium reaches (or
exceeds) the pH threshold, the second polymeric material becomes
soluble.
Throughout the specification, the term "insoluble" is used to mean
that 1 g of a polymeric material requires more than 10,000 ml of
solvent or "surrounding medium" to dissolve at a given pH. In
addition, the term "soluble" is used to mean that 1 g of a
polymeric material requires less than 10,000 ml, preferably less
than 5,000 ml, more preferably less than 1000 ml, even more
preferably less than 100 ml or 10 ml of solvent or surrounding
medium to dissolve at a given pH.
By "surrounding medium", the Inventors mean gastric fluid and
intestinal fluid, or an aqueous solution designed to recreate in
vitro gastric fluid or intestinal fluid.
The normal pH of gastric juice is usually in the range of pH 1 to
3. The second polymeric material is insoluble below pH 5 and
soluble at about pH 5 or above and, thus, is usually insoluble in
gastric juice. Such a material may be referred to as a
gastro-resistant material or an "enteric" material.
The second polymeric material has a pH threshold of pH 5 or above,
e.g. about pH 5.5 or above, preferably about pH 6 or above and more
preferably about pH 6.5 or above. The second polymeric material
typically has a pH threshold of no more than about pH 8, e.g. no
more than about pH 7.5 and preferably no more than about pH 7.2.
Preferably, the second polymeric material has a pH threshold within
the range of pH found in intestinal fluid. The pH of intestinal
fluid may vary from one person to the next, but in healthy humans
is generally from about pH 5 to 6 in the duodenum, from about 6 to
8 in the jejunum, from about 7 to 8 in the ileum, and from about 6
to 8 in the colon.
For embodiments in which initial release is intended for the small
intestine, the second polymeric material preferably has a pH
threshold of about pH 5.5, and more preferably has a pH threshold
of about pH 6. For embodiments in which initial release is intended
for the colon, the second polymeric material preferably has a pH
threshold of about pH 6.5, and more preferably has a pH threshold
of about pH 7.
The pH threshold at which a material becomes soluble may be
determined by a simple titration technique which would be part of
the common general knowledge to the person skilled in the art.
The second polymeric material is typically a film-forming polymeric
material such as a polymethacrylate polymer, a cellulose polymer or
a polyvinyl-based polymer. Examples of suitable cellulose polymers
include cellulose acetate phthalate (CAP); cellulose acetate
trimellitate (CAT); Hydroxypropylmethylcellulose phthalate (HPMCP)
and hydroxypropylmethylcellulose acetate succinate (HPMC-AS).
Examples of suitable polyvinyl-based polymers include polyvinyl
acetate phthalate (PVAP).
The second material is preferably an "anionic" polymeric material,
i.e. a polymeric material containing groups that are ionisable in
aqueous media to form anions (see below), and more preferably a
co-polymer of a (meth)acrylic acid and a (meth)acrylic acid
C.sub.1-4 alkyl ester, for example, a copolymer of methacrylic acid
and methacrylic acid methyl ester. Such a polymer is known as a
poly(methacrylic acid/methyl methacrylate) co-polymer. Suitable
examples of such co-polymers are usually anionic and not sustained
release polymethacrylates. The ratio of carboxylic acid groups to
methyl ester groups (the "acid:ester ratio") in these co-polymers
determines the pH at which the co-polymer is soluble. The
acid:ester ratio may be from about 2:1 to about 1:3, e.g. about 1:1
or, preferably, about 1:2. The molecular weight ("MW") of preferred
anionic co-polymers is usually from about 120,000 to 150,000 g/mol,
preferably about 125,000 g/mol or about 135,000 g/mol.
Preferred anionic poly(methacrylic acid/methyl methacrylate)
co-polymers have a molecular weight of about 125,000 g/mol.
Suitable examples of such polymers have an acid:ester ratio of
about 1:1 and a pH threshold of about pH 6, or have an acid:ester
ratio of about 1:2 and a pH threshold of about pH 7.
A specific example of a suitable anionic poly(methacrylic
acid/methyl methacrylate) co-polymer having a molecular weight of
about 125,000 g/mol, an acid:ester ratio of about 1:1 and a pH
threshold of about pH 6 is sold under the trade mark Eudragit.RTM.
L. This polymer is available in the form of a powder (Eudragit.RTM.
L 100), or as an organic solution (12.5%) (Eudragit.RTM. L
12.5).
A specific example of a suitable anionic poly(methacrylic
acid/methyl methacrylate) co-polymer having a molecular weight of
about 125,000 g/mol, an acid:ester ratio of about 1:2 and a pH
threshold of about pH 7 is sold under the trade mark Eudragit.RTM.
S. This polymer is available in the form of a powder (Eudragit.RTM.
S 100) or as an organic solution (12.5%) (Eudragit.RTM. S
12.5).
The second polymeric material may be a co-polymer of methacrylic
acid and ethyl acrylate. Preferred poly(methacrylic acid/ethyl
acrylate) co-polymers have a molecular weight from about 300,000 to
350,000 g/mol, e.g. about 320,000 g/mol. Suitable examples of such
co-polymers have an acid:ester ratio of about 1:1 and a pH
threshold of about pH 5.5.
A specific example of a suitable anionic poly(methacrylic
acid/ethyl acrylate) co-polymer is available in the form of a
powder and sold under the trade mark Eudragit.RTM. L 100-55, or in
the form of an aqueous dispersion (30%) and sold under the trade
mark Eudragit.RTM. L 30 D-55.
The second polymeric material may be a co-polymer of methyl
acrylate, methyl methacrylate and methacrylic acid. Preferred
poly(methyl acrylate/methyl methacrylate/methacrylic acid)
co-polymers have a molecular weight from about 250,000 to about
300,000 g/mol, e.g. about 280,000 g/mol. Suitable examples of such
co-polymers have a methyl acrylate:methyl methacrylate:methacrylic
acid ratio of about 7:3:1 thereby providing an acid:ester ratio of
about 1:10 and a pH threshold of about pH 7.
A specific example of a suitable anionic poly(methyl
acrylate/methyl methacrylate/ethyl acrylate) co-polymer is
available in the form of an aqueous dispersion (30%) and is sold
under the trade mark Eudragit.RTM. FS 30 D.
The Eudragit.RTM. co-polymers are manufactured and/or distributed
by Evonik GmbH, Darmstadt, Germany.
Mixtures of film forming polymer materials may be used as
appropriate. For example, the second polymeric material may be a
blend of at least two different polymers having a pH threshold of
about pH 5 and above. Preferably, the polymers in the blend are
different polymethacrylate polymers. In embodiments where the
second polymeric material is a blend of two different polymers
having a pH threshold of about pH 5 or above, the polymers may be
present in the blend in a polymer weight ratio from about 1:99 to
about 99:1, e.g. from about 10:90 to about 90:10, or from 25:75 to
about 75:25, or from about 40:60 to about 60:40, for example about
50:50.
An example of a suitable mixture would include a mixture, e.g. a
1:1 mixture, of Eudragit.RTM. L and Eudragit.RTM. S. A further
example would include a blend, e.g. a 50:50 blend, of Eudragit S
and Eudragit FS.
For the avoidance of doubt, the terms "mixture" and "blend" in the
context of mixtures or blends of polymers forming the second
polymeric material, are used herein interchangeably.
However, the use of a particular film forming polymer material,
e.g. a poly(methacrylic acid/methyl methacrylate) co-polymer, alone
is preferred. The use of Eudragit.RTM. S alone as the second
polymeric material is particularly preferred for colonic release
formulations.
Outer Layer
In some preferred embodiments, the pH dependently soluble (or
second) polymeric material(s) is/are present in the outer layer as
the sole film-forming polymeric material(s). In other preferred
embodiments, the pH dependently soluble (or second) polymeric
material(s) is/are present in the outer layer in admixture with the
digestible (or first) polymeric material(s) which is susceptible to
attack by colonic bacteria.
In embodiments in which the outer layer comprises a mixture of
first and second polymeric materials, the proportion of the first
polymeric material to the second polymeric material is typically at
least 1:99, e.g. at least 10:90 and preferably at least 25:75. The
proportion is typically no more than 99:1, e.g. no more than 75:25
and preferably no more than 60:40. In some embodiments, the
proportion may be no more than 35:65. In some preferred
embodiments, the proportion is from 10:90 to 75:25, e.g. from 10:90
to 60:40 and preferably from 25:75 to 60:40. In some particularly
preferred embodiments, the proportion is from 15:85 to 35:65, e.g.
from 25:75 to 35:65 and preferably about 30:70. In other
particularly preferred embodiments, the proportion is from 40:60 to
about 60:40, e.g. about 50:50.
The mixture of first and second polymeric materials is preferably
substantially homogenous.
Optionally, conventional excipients such as those excipients
selected from plasticisers for film formation (for example,
triethyl citrate), anti-tack agents (such as glyceryl monostearate
or GMS) and surfactants (such as polysorbate 80), may be included
in amounts up to 30 wt % of the final composition of the outer
coating preparation.
The thickness of the outer coating of the core is typically from
about 10 .mu.m to about 150 .mu.m. The thickness of a specific
coating will, however, depend on the composition of the coating.
For example, coating thickness is directly proportional to the
amount of polysaccharide in the coating. Thus, in embodiments where
the coating comprises high amylose starch and Eudragit.TM. S at a
ratio of about 30:70, the coating thickness may be from about 70
.mu.m to about 130 .mu.m, and preferably from about 90 .mu.m to
about 110 .mu.m.
The coating amount of the polymeric material(s) in the outer
coating is typically from about 2 mg/cm.sup.2 to about 10
mg/cm.sup.2, preferably from about 2 mg/cm.sup.2 to about 8
mg/cm.sup.2, and most preferably from about 4 mg/cm.sup.2 to about
8 mg/cm.sup.2, based on the dry weight of the total polymeric
material. These values are particularly appropriate for cores
having a diameter from about 5.times.10.sup.-4 m to about 25
mm.
Soluble (or Third) Polymeric Material
The formulation according to the present invention additionally has
an inner layer which is positioned between the isolation layer and
the outer layer. The inner layer comprises a third polymeric
material which may be insoluble in gastric fluid and soluble in
intestinal fluid, but preferably is soluble in both gastric fluid
and intestinal fluid (referred herein as gastrointestinal
fluid).
By "gastric fluid", the inventors mean the aqueous fluid in the
stomach of a mammal, particularly a human. The fluid contains up to
about 0.1 N hydrochloric acid and substantial quantities of
potassium chloride and sodium chloride, and plays a key role in
digestion by activating digestive enzymes and denaturing ingested
protein. Gastric acid is produced by cells lining the stomach and
other cells produce bicarbonate which acts as a buffer to prevent
the gastric fluid from becoming too acidic.
By "intestinal fluid", the Inventors mean the fluid in the lumen of
the intestine of a mammal, particularly a human. Intestinal fluid
is a pale yellow aqueous fluid secreted from glands lining the
walls of the intestine. Intestinal fluid includes fluid found in
the small intestine, i.e. fluid found in the duodenum (or "duodenal
fluid"), fluid found in the jejunum (or "jejunal fluid") and fluid
found in the ileum (or "ileal fluid"), and fluid found in the large
intestine, e.g. "colonic fluid".
The skilled person can readily determine whether a polymer is
soluble in gastric fluid and/or intestinal fluid. If a polymer is
soluble in water (or aqueous solution), e.g. a buffer solution) at
a pH from 1 to 3, then that polymer would typically be soluble in
gastric fluid. Similarly if a polymer is soluble in water (or
aqueous solution, e.g. a buffer solution) at a pH from 5 to 8, then
that polymer would typically be soluble in intestinal fluid.
Alternatively, the compositions of gastric fluid and intestinal
fluid are known and may be replicated in vitro. If a polymer is
soluble in artificial gastric fluid or intestinal fluid in vitro,
then it would typically be soluble in gastric fluid or intestinal
fluid respectively in vivo.
Any pharmacologically acceptable water soluble film forming
polymers are, in principle, suitable for use as the third polymeric
material. The solubility of the water soluble polymers may be
dependent on pH, i.e. the third polymeric material may be a pH
sensitive polymer having a pH threshold. In such embodiments, the
pH threshold of the third polymeric material is less than,
typically at least 0.5 pH units less than and preferably from 0.5
to 3.5 pH units less than, the pH threshold of the second polymeric
material. The pH threshold of the third polymeric material is
typically from about pH 4.5 to about pH 7.5.
The third polymeric material may be soluble in at least one fluid
selected from gastric fluid, duodenal fluid, jejunal fluid and
ileal fluid. However, in preferred embodiments, the solubility of
the third polymeric material in water is not dependent on pH; at
least not within the range of pH found in the intestine. In
preferred embodiments, the third polymeric material is soluble in
fluid at any point in the stomach and intestine, i.e. in
gastrointestinal fluid.
Suitable polymers for use as the third polymeric material
preferably contain groups that are ionisable in aqueous media to
form anions. Such polymers are known in the art as "anionic"
polymers. Suitable anionic polymers include polycarboxylic acid
polymers, i.e. polymers or co-polymers that contain a plurality of
carboxylic acid functional groups that are ionisable in aqueous
media such as intestinal fluid, to form carboxylate anions.
In embodiments in which the third polymeric material is a
polycarboxylic acid polymer, it is preferred that the third
polymeric material is at least partially neutralised, i.e. that at
least a portion, e.g. at least 10%, preferably at least 25%, more
preferably at least 50%, and most preferably at least 90%, of the
carboxylic acid groups in are the form of carboxylate anions. In
particularly preferred embodiments, all of the carboxylic acid
groups in the third polymeric material are in the form of
carboxylate anions. Such polymers are referred to herein as "fully
neutralised".
In preferred embodiments, the second and third polymeric materials
are based on the same polycarboxylic acid polymer with the third
polymeric material having a higher degree of neutralisation than
the second polymeric material. For example, for a particular
polycarboxylic acid polymer, the second polymeric material may be
in non-neutralised form with the third polymeric material in
partially or fully neutralised form. Alternatively, the second
polymeric material may be in partially neutralised form, with the
third polymeric material also in partially neutralised form
(although partially neutralised to a greater extent), or in fully
neutralised form.
Examples of suitable polycarboxylic acid polymers include cellulose
acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP),
hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl
methylcellulose acetate succinate (HPMC-AS), cellulose acetate
trimellitate (CAT), xanthan gum, alginates and shellac. However,
the polycarboxylic acid polymer is preferably selected from
co-polymers of a (meth)acrylic acid and a (meth)acrylic acid alkyl,
e.g. C.sub.1-4 alkyl, ester and a copolymer of methacrylic acid and
methacrylic acid methyl ester is particularly suitable. Such a
polymer is known as a poly(methacrylic acid/methyl methacrylate)
co-polymer or a "polymethacrylate". The ratio of carboxylic acid
groups to methyl ester groups (the "acid:ester ratio") in these
co-polymers determines the pH at which the co-polymer is soluble.
The acid:ester ratio may be from about 2:1 to about 1:3, e.g. about
1:1 or, preferably, about 1:2. The molecular weight ("MW") of
preferred anionic co-polymers is usually from about 120,000 to
150,000, preferably about 125,000 or about 135,000.
Preferred co-polymers for the third polymeric material are
discussed in detail in the section above relating to the second
polymeric material, and include Eudragit.RTM. L; Eudragit.RTM. S;
Eudragit.RTM. FS 30 D; Eudragit.RTM. L30D-55; and Eudragit.RTM.
L100-55.
The exemplary polymers may be used as the third polymeric material
in non-neutralised form (provided the pH threshold of the polymer
is less than the pH threshold of the second polymeric material--see
above) or may be used in at least partially, more preferably fully,
neutralised form.
Partially neutralised polymers suitable for use as the third
polymeric material, and their methods of production, are known in
the art, for example from US2008/0200482A and WO2008/135090A. These
polymers may be fully neutralised by the addition of further base
to the coating solutions.
In preferred embodiments, the third polymeric material is an at
least partially, preferably fully, neutralised co-polymer of
(meth)acrylic acid and a (meth)acrylic acid C.sub.1-4 alkyl ester.
In particularly preferred embodiments, the third polymeric material
is a fully neutralised co-polymer of (meth)acrylic acid and
(meth)acrylic acid methyl ester, particularly Eudragit.RTM. S.
The Inventors have observed that fully neutralised Eudragit.RTM. S
is capable of forming a film and is readily and completely soluble
in water independently of at least the range of pH found in the
intestine, e.g. about pH 5 to about pH 8. Fully neutralised
Eudragit.RTM. S is particularly preferred for use as the third
polymeric material in the present invention.
Other polymers suitable for use as the third polymeric material
include pharmacologically acceptable non-ionic polymers, i.e.
pharmacologically acceptable polymers which do not ionise in
aqueous media. In these embodiments, the inner layer additionally
comprises at least one additive selected from a buffer agent and a
base. In particular, the inner layer of these embodiments
preferably comprises a base and, optionally, a buffer agent. In
preferred embodiments, the inner layer comprises both a buffer
agent and a base. Suitable examples of buffer agents and bases are
discussed below.
Examples of suitable non-ionic polymers include methylcellulose
(MC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose
(HPMC), poly(ethylene oxide)-graft-polyvinyl alcohol,
polyvinylpyrrolidinone (PVP) and polyvinyl alcohol (PVA).
Mixtures of film forming polymer materials may be used as
appropriate. The polymer components in such mixtures may be anionic
polymers, non-ionic polymers, or a mixture of anionic and non-ionic
polymers. An example of a suitable mixture would include a mixture,
e.g. a 1:1 mixture, of Eudragit.RTM. L and Eudragit.RTM. S, and a
mixture, e.g. a 1:1 mixture, of Eudragit.RTM. S and HPMC. However,
the use of a particular film forming polymeric material alone, e.g.
a poly(methacrylic acid/methyl methacrylate) co-polymer and
Eudragit.RTM. S in particular, is preferred.
Base
In preferred embodiments, the inner layer comprises at least one
base. The purpose of the base is to provide an alkaline environment
on the underside of the outer layer once intestinal fluid begins to
penetrate the outer layer. Without being bound by any particular
theory, the Inventors believe that the alkaline environment
facilitates dissolution of the outer layer and thereby also
disintegration of the outer layer since the pH of the alkaline
environment is above the pH threshold of the second polymeric
material, thereby accelerating release of the drug from the
formulation.
In principle, any pharmacologically acceptable base may be used.
The base is typically a non-polymeric compound. Suitable bases
include inorganic bases such as sodium hydroxide, potassium
hydroxide and ammonium hydroxide, and organic bases such as
triethanolamine, sodium bicarbonate, potassium carbonate, trisodium
phosphate, trisodium citrate or physiologically tolerated amines
such as triethylamine. Hydroxide bases in general, and sodium
hydroxide in particular, are preferred.
In embodiments in which the third polymeric material is a fully
neutralised polycarboxylic acid polymer, the base entrapped within
the inner layer is usually the base that was used to neutralise the
polymer and to adjust the pH of the inner coating preparation to a
pH from about pH 5.5 to about pH 10, e.g. about pH 7.5 to about pH
10 (see below).
In embodiments in which the third polymeric material is a non-ionic
polymer, the inner layer usually comprises either a base, or more
typically a combination of a base and a buffer agent.
The amount of base present in the inner layer would depend at least
in part on the final pH of the inner coating preparation prior to
coating a given batch of cores; the number of cores to be coated in
the batch; the amount of the inner coating preparation used in the
coating process of the batch; and the efficiency of the coating
process in terms of the amount of wasted coating preparation.
Buffer Agent
The inner coating preferably comprises at least one buffer agent.
The purpose of the buffer agent is to provide or increase pH/buffer
capacity on the underside of the outer layer once intestinal fluid
begins to penetrate the outer layer. Without wishing to be bound by
any particular theory, the Inventors believe that the buffer agent
increases the buffer capacity in the dissolving inner layer and
assists the ionisation and dissolution of the polymer(s) in the
outer layer. It is believed that, for a given pH, the higher the
buffer capacity, the faster the rate of polymer dissolution. In
embodiments where there is a base in the inner layer, the buffer
agent helps maintains the alkaline environment under the outer
layer once intestinal fluid penetrates the outer layer.
The buffer agent may be an organic acid such as a pharmacologically
acceptable non-polymeric carboxylic acid, e.g. a carboxylic acid
having from 1 to 16, preferably 1 to 3, carbon atoms. Suitable
carboxylic acids are disclosed in WO2008/135090A. Citric acid is an
example of such a carboxylic acid. The carboxylic acids may be used
in carboxylate salt form, and mixtures of carboxylic acids,
carboxylate salts or both may also be used.
The buffer agent may also be an inorganic salt such as an alkali
metal salt, an alkali earth metal salt, an ammonium salt, and a
soluble metal salt. As metals for the soluble metal salts,
manganese, iron, copper, zinc and molybdenum can be mentioned.
Further preferred, the inorganic salt is selected from chloride,
fluoride, bromide, iodide, phosphate, nitrate, nitrite, sulphate
and borate. Phosphates such as potassium dihydrogen phosphate are
preferred over other inorganic buffer salts and organic acid
buffers due to their greater buffer capacity at the pH of the
coating solution, for example pH 8.
The buffer agent(s) is usually present in the inner layer in an
amount from about 0.1 wt %) to about 50 wt %. In embodiments in
which the soluble (or third) polymeric material is an at least
partially neutralised polycarboxylic acid, the buffer agent(s) is
usually present in the inner layer in an amount from about 0.1 to
about 20 wt %, e.g. from about 0.1 to about 4 wt %, preferably from
about 0.1 to about 3 wt %, and more preferably about 1 wt %, based
on the dry weight of the third polymeric material. In embodiments
in which the soluble (or third) polymeric material is a non-ionic
polymer, the buffer agent(s) is usually present in an amount from
about 10 wt % to 30 wt %, based on the dry weight of the third
polymeric material.
Inner Layer
In addition to the buffer agent and/or the base, the inner layer
may comprise conventional excipients for polymer films, including
those excipients selected from plasticizers (such a triethyl
citrate), anti-tack agents (such as GMS), and surfactants (such as
polysorbate 80).
The thickness of the inner coating of the core is typically from
about 10 .mu.m to about 150 .mu.m. The inner layer typically has a
polymer coating amount from about 2 mg/cm.sup.2 to about 10
mg/cm.sup.2, preferably from about 2 mg/cm.sup.2 to about 8
mg/cm.sup.2, and most preferably from about 3 mg/cm.sup.2 to about
7 mg/cm.sup.2, based on the dry weight of the third polymeric
material, particularly for cores having a diameter from about 0.2
mm to about 30 mm.
Optional Additional Layers
The formulation of the present invention may have a top coating
layer coating the outer layer. The formulation may also comprise an
intermediate layer between the outer and inner layers, provided
that the intermediate layer does not affect adversely the release
characteristics of the formulation. However, the outer layer is
usually provided in contact with the inner layer, that is to say
the outer layer is usually applied directly on to the inner layer,
i.e. there is usually no intermediate layer separating the inner
and outer layers.
The Core
The "core" is the solid body on which the inner layer is applied.
The core may be any suitable dosage form, for example, a tablet, a
pellet, a granule, a microparticle, a hard or soft capsule, or a
microcapsule. In preferred embodiments, the core is a tablet or a
capsule.
The invention has application in embodiments in which the core is
compatible with the inner layer which is typically alkaline, or
provides an alkaline environment on exposure to moisture. Such
embodiments are likely to include cases where the core is neutral,
or is at neutral pH. However, the invention has particular
application in embodiments in which the core or components within
the core are incompatible with the inner layer. Such embodiments
are likely to include cases where the core is acidic, or is at an
acidic pH. Such an acidic core would not be compatible with an
alkaline inner layer and the isolation layer would have the added
benefit of preventing unwanted interaction between the core and the
inner layer.
The core comprises the drug(s). The drug(s) may be contained within
the body of the core, for example within the matrix of a tablet or
pellet, or within the contents encapsulated within a capsule.
Alternatively, the drug may be in a coating applied to the core,
for example where the core is a bead of edible material such as
sugar, e.g. where the core is in the form of a nonpareil bead or
dragee. The core may be "acidic" because the drug or any component
within the core comprises at least one acidic group.
The core may consist of the drug(s) alone, or more usually may
consist of the drug(s) and at least one pharmacologically
acceptable excipient. In this connection, the core is typically a
tablet or pellet and consists of a mixture of the drug(s) with a
filler or diluent material, e.g. lactose or cellulose material such
as microcrystalline cellulose; a binder, e.g. polyvinylpyrrolidone
("PVP") or hydroxypropyl methylcellulose (HPMC); a disintegrant,
e.g. croscarmellose sodium (e.g. Ac-Di-Sol.TM.) and sodium starch
glycolate (e.g. Explotab.TM.); and/or a lubricant, e.g. magnesium
stearate and talc. The core may be a compressed granulate
comprising at least some of these materials.
The minimum diameter of each core is typically at least about
10.sup.-4 m, usually at least about 5.times.10.sup.-4 m and,
preferably, at least about 10.sup.-3 m. The maximum diameter is
usually no more than 30 mm, typically no more than 25 mm and,
preferably, no more than 20 mm. In preferred embodiments, the core
has a diameter from about 0.2 mm to about 25 mm, and preferably
from about 0.2 mm to about 4 mm (e.g. for pellets or mini-tablets)
or from about 15 mm to about 25 mm (e.g. for certain tablets or
capsules). The term "diameter" refers to the largest linear
dimension through the core.
The formulation may comprise a plurality of coated cores in order
to provide a single dose of the drug(s), particularly in
embodiments in which the core is "small", e.g. having a diameter of
less than 5 mm. Multiunit dosage forms comprising coated cores
having a diameter of less than 3 mm may be preferred.
The present invention has application in a multi-phasic drug
release formulation comprising at least two pluralities of coated
cores, e.g. coated pellets, in the same dosage form, e.g. a
capsule, in which the coated cores of one plurality are
differentiated from the coated cores of the or each other plurality
by the coating. The coatings may differ from one plurality to the
next in terms of coating thickness or composition, e.g. the ratio
and/or identity of components. Multi-phasic drug release
formulations would be particularly suitable for suffers of Crohn's
disease affecting different regions along the intestine.
Release from formulations according to the present invention is
typically delayed until the proximal small intestine, usually at
least the distal ileum and, preferably, the colon. Release from
certain formulations may also be sustained. However, in preferred
formulations, release is pulsatile.
The time between initial exposure to conditions suitable for drug
release and the start of drug release is known as the "lag time".
The lag time depends on a number of factors including coating
thickness and composition and may vary from one patient to the
next. Formulations according to the present invention usually
display a lag time in colonic conditions of at least 10 minutes. In
most embodiments, the lag time is from about 10 minutes to about 8
hours. For example, the lag time in faecal slurry at pH 6.8 may be
from about 10 minutes to about 2 hours, e.g. from about 30 minutes
to about 1.5 hours. Complete release of the drug may be achieved in
no more than 5 hours, e.g. no more than 4 hours, after exposure to
these conditions.
A formulation is usually defined as gastric resistant if there is
less than 10 wt % drug release in acidic media after 2 hours.
Formulations according to the present invention typically display
far less than 10 wt % drug release in acidic media and may be
considered to be gastric resistant. The formulations usually
display less than 1 wt % drug release in acidic media and,
typically, display substantially no drug release in acidic media.
When starch is combined with an acrylate film forming material to
form the outer layer of the coating for the core, typically less
than 5% drug release occurs over 5 hours in conditions simulating
the stomach and small intestine.
In one embodiment, the core is a tablet having a diameter of 15-25
mm. The outer layer preferably comprises a 30:70 mixture of high
amylose starch, e.g. Eurylon.TM. VII or VI, and a polymethacrylate
polymer, e.g. Eudragit.TM. S, and the inner layer preferably
comprises a fully neutralized polymethacrylate polymer, e.g.
Eudragit.TM. S, applied from an inner coating preparation having a
pH of about 8. The core is preferably coated with the inner layer
to a thickness from about 3 to about 7 mg/cm.sup.2 (based on dry
weight of the polymethacrylate polymer) to form an inner layer
coated core, which is then coated with the outer layer to a
thickness from about 4 to about 8 mg/cm.sup.2 (based on dry weight
of polymethacrylate polymer).
Different Aspects
Release of a drug in the colon may be considered to be a medical
method under a broad definition of the term. However, in the
absence of treatment of a particular indication, acceleration of
initial drug release in the colon may be viewed as a non-medical
technical effect. Accordingly, there is provided, by way of a
second aspect of the present invention, a non-medical use of an
isolation layer to accelerate drug release in the intestine of a
subject from a delayed release drug formulation for oral
administration to said subject, said formulation comprising: a core
comprising said drug; said isolation layer coating said core; and
an outer coating for providing intestinal release of said drug,
said outer coating comprising an outer layer and an inner layer,
wherein the outer layer comprises a pH dependently soluble
polymeric material which has a pH threshold at about pH 5 or above,
and wherein the inner layer comprises a soluble polymeric material
which is soluble in intestinal fluid or gastrointestinal fluid,
said soluble polymeric material being selected from the group
consisting of a polycarboxylic acid polymer that is at least
partially neutralised, and a non-ionic polymer, provided that,
where said soluble polymeric material is a non-ionic polymer, said
inner layer comprises at least one additive selected from a buffer
agent and a base.
According to a third aspect of the present invention, there is
provided a method of accelerating drug release in the colon of a
subject from a delayed release drug formulation for oral
administration to said subject, said formulation comprising: a core
comprising said drug; and an outer coating for providing intestinal
release of said drug, said outer coating comprising an outer layer
and an inner layer, wherein the outer layer comprises a pH
dependently soluble polymeric material which has a pH threshold at
about pH 5 or above, and wherein the inner layer comprises a
soluble polymeric material which is soluble in intestinal fluid or
gastrointestinal fluid, said soluble polymeric material being
selected from the group consisting of a polycarboxylic acid polymer
that is at least partially neutralised, and a non-ionic polymer,
provided that, where said soluble polymeric material is a non-ionic
polymer, said inner layer comprises at least one additive selected
from a buffer agent and a base, said method comprising providing an
isolation layer between said core and said outer coating.
According to a fourth aspect of the present invention, there is
provided a method of producing a delayed release drug formulation
for oral administration, wherein said formulation provides
accelerated release of a drug in the intestine of a subject, said
method comprising: providing a core comprising said drug; coating
said core with an isolation layer to produce an isolation layer
coated core; and coating said isolation layer coated core with an
outer coating for providing intestinal release of said drug, said
outer coating comprising an outer layer and an inner layer, wherein
the outer layer comprises a pH dependently soluble polymeric
material which has a pH threshold at about pH 5 or above, and
wherein the inner layer comprises a soluble polymeric material
which is soluble in intestinal fluid or gastrointestinal fluid,
said soluble polymeric material being selected from the group
consisting of a polycarboxylic acid polymer that is at least
partially neutralised, and a non-ionic polymer, provided that,
where said soluble polymeric material is a non-ionic polymer, said
inner layer comprises at least one additive selected from a buffer
agent and a base,
The Inventors have developed some new formulations that are not
disclosed in the art and which demonstrate unexpected acceleration
of initial drug release after exposure to the typical pH conditions
of the colon. The formulations in question use the pH dependently
soluble (or second) polymeric material as the sole film-forming
material in the outer layer. Thus, according to a fifth aspect of
the present invention, there is provided a delayed release drug
formulation for oral administration to deliver a drug to the
intestine of a subject, said formulation comprising: a core
comprising said drug; said isolation layer coating said core; and
an outer coating for providing intestinal release of said drug,
said outer coating comprising an outer layer and an inner layer,
wherein the outer layer comprises a film-forming polymeric material
consisting of a pH dependently soluble polymeric material which has
a pH threshold at about pH 5 or above, wherein the inner layer
comprises a soluble polymeric material which is soluble in
intestinal fluid or gastrointestinal fluid, said soluble polymeric
material being selected from the group consisting of a
polycarboxylic acid polymer that is at least partially neutralised,
and a non-ionic polymer, provided that, where said soluble
polymeric material is a non-ionic polymer, said inner layer
comprises at least one additive selected from a buffer agent and a
base. Release of the drug in the colon from these formulations is
typically accelerated as described above.
In addition, according to a sixth aspect of the present invention,
there is provided a delayed release drug formulation for oral
administration to deliver a drug to the intestine of a subject,
said formulation comprising: a core comprising said drug; said
isolation layer coating said core; and an outer coating for
providing intestinal release of said drug, said outer coating
comprising an outer layer and an inner layer, wherein the outer
layer comprises a pH dependently soluble polymeric material which
has a pH threshold at about pH 5 or above, wherein the inner layer
comprises a soluble polymeric material which is soluble in
intestinal fluid or gastrointestinal fluid, said soluble polymeric
material being selected from the group consisting of a
polycarboxylic acid polymer that is at least partially neutralised,
and a non-ionic polymer, provided that, where said soluble
polymeric material is a non-ionic polymer, said inner layer
comprises at least one additive selected from a buffer agent and a
base, and wherein release of said drug in the intestine is
accelerated.
As described above, the Inventors have discovered that the use of
an isolation layer also improves the stability of the formulation
during storage. In this regard, according to a seventh aspect of
the present invention, there is provided use of an isolation layer
to prevent deceleration of drug release in the intestine of a
subject from a delayed release drug formulation for oral
administration to said subject after storage, said formulation
comprising: a core comprising said drug; said isolation layer
coating said core; and an outer coating for providing intestinal
release of said drug, said outer coating comprising an outer layer
and an inner layer, wherein the outer layer comprises a pH
dependently soluble polymeric material which has a pH threshold at
about pH 5 or above, and wherein the inner layer comprises a
soluble polymeric material which is soluble in intestinal fluid or
gastrointestinal fluid, said soluble polymeric material being
selected from the group consisting of a polycarboxylic acid polymer
that is at least partially neutralised, and a non-ionic polymer,
provided that, where said soluble polymeric material is a non-ionic
polymer, said inner layer comprises at least one additive selected
from a buffer agent and a base.
For colonic release formulations, lag time (T.sub.lag) in vitro in
Krebs buffer at pH 7.4 after 2 h at 0.1M HCl is typically increased
after storage by no more than 5%. In absolute terms, lag time
(T.sub.lag) in vitro in Krebs buffer at pH 7.4 after 2 h at 0.1M
HCl is typically increased after storage by no more than 10 minutes
and preferably by no more than 5 minutes.
The effect typically results after storage in closed high density
polyethylene (HDPE) containers for at least 1 month at 40.degree.
C./75% RH and/or after storage in closed HDPE containers for at
least 3 months at 25.degree. C./60% RH, and is particularly
significant when the isolation layer comprises HPMC. Additionally
or alternatively, the outer layer preferably comprises the pH
dependently soluble polymeric material in admixture with a
digestible polymeric material susceptible to attack by colonic
bacteria.
In the second to seventh aspects of the present invention, the
formulation may be as defined in any of the embodiments defined in
respect of the first aspect.
According to a further aspect of the present invention, there is
provided a formulation according any previous aspect for use in a
method of medical treatment of the human or animal body by
therapy.
The core comprises at least one drug. The formulation is usually
used to administer a single drug as the sole therapeutically active
component. However, more than one drug may be administered in a
single formulation.
The formulation of the present invention is designed to administer
a wide range of drugs. Suitable drugs include those drugs which are
known for intestinal administration using known delayed release
oral formulations. The present invention may be used to administer
drugs having a local or a systemic effect.
The formulation of the present invention has particular application
in the intestinal administration of a drug comprising at least one
acidic group such as a carboxylic acid group. Such drugs may be
acidic drugs or zwitterionic drugs. An example of such a drug is
5-aminosalicylic acid (5ASA or mesalazine).
The identity of the drug(s) in the formulation obviously depends on
the condition to be treated. In this connection, the formulation
has particular application in the treatment of IBD (including
Crohn's disease and ulcerative colitis); IBS; constipation;
diarrhoea; infection; and carcinoma, particularly colon or
colorectal cancer.
For the treatment or prevention of IBD, the formulation may
comprise at least one drug selected from the group consisting of
anti-inflammatory agents (e.g. 5ASA (otherwise known as mesalazine
or mesalamine), 4ASA, sulphasalazine and balsalazide);
non-steroidal anti-inflammatory agents (e.g. ibuprofen and
diclofenac); steroids (e.g. prednisolone; budesonide or
fluticasone); immunosuppressants (e.g. azathioprine; cyclosporin;
and methotrexate); antibiotics; and biological agents including
peptides, proteins and antibody fragments. Suitable examples of
biological agents include alkaline phosphatase and anti-TNF
antibodies such as infliximab, adalimumab, certulizumab pegol,
golimumab and ustekinumab.
For the treatment or prevention of cancer, the formulation may
comprise at least one antineoplastic agent. Suitable antineoplastic
agents include fluorouracil; methotrexate; dactinomycin; bleomycin;
etoposide; taxol; vincristine; doxorubicin; cisplatin;
daunorubicin; VP-16; raltitrexed; oxaliplatin; and
pharmacologically acceptable derivatives and salts thereof. For the
prevention of colon cancer or colorectal cancer, primarily in
patients suffering from colitis, the formulation may comprise the
anti-inflammatory agent, 5ASA.
For the treatment or prevention of IBS, constipation, diarrhoea or
infection, the formulation may comprise at least one active agent
suitable for the treatment or prevention of these conditions.
Pharmacologically acceptable derivatives and/or salts of the drugs
may also be used in the formulation. An example of a suitable salt
of prednisolone is methyl prednisolone sodium succinate. A further
example is fluticasone propionate.
The present invention has particular application in either the
treatment of IBD (particularly, ulcerative colitis) or the
prevention of colon cancer or colorectal cancer (primarily in
colitis patients), both using 5ASA. It also has application as a
portal of entry of drugs into the systemic circulation via the
colon. This is particularly advantageous for peptide and protein
drugs which are unstable in the upper gastrointestinal tract. The
present invention may also be utilised for the purpose of
chronotherapy.
In another aspect of the invention, there is provided a method of
targeting a drug to the colon comprising administering to a patient
a formulation as defined above.
In a yet further aspect of the invention, there is provided the use
of a formulation as defined above in the manufacture of a
medicament for the treatment or prevention of IBD (particularly
ulcerative colitis); IBS; constipation; diarrhoea; infection; and
cancer.
There is also provided the use of at least one drug selected from
anti-inflammatory agents and steroids in the manufacture of a
medicament comprising a formulation as defined above for use in the
treatment of IBD. In addition, there is also provided the use of at
least one antineoplastic agent in the manufacture of a medicament
comprising a formulation as defined above for use in the treatment
of carcinoma. Further, there is also provided use of 5ASA in the
manufacture of a medicament comprising a formulation as defined
above for use in the prevention of colon cancer or colorectal
cancer.
According to a still further aspect of the present invention, there
is provided a method of medical treatment or prevention of IBD or
carcinoma comprises administering to a patient a therapeutic amount
of a formulation as defined above.
The formulation will typically comprise a therapeutically effective
amount of the or each drug which may be from about 0.01 wt % to
about 99 wt %, based on the total weight of the formulation. The
actual dosage would be determined by the skilled person using his
common general knowledge. However, by way of example, "low" dose
formulations typically comprise no more than about 20 wt % of the
drug, and preferably comprise from about 1 wt % to about 10 wt %,
e.g. about 5 wt %, of the drug. "High" dose formulations typically
comprise at least 40 wt % of the drug, and preferably from about 45
wt % to about 85 wt %, e.g. about 50 wt % or about 80 wt %.
Method
In preferred embodiments, the method of producing a delayed release
drug formulation for oral administration to deliver a drug to the
colon typically comprises: forming a core comprising a drug;
coating the core with an isolation layer to form an isolated core;
coating the isolated core using an inner coating preparation
comprising the soluble (or third) polymeric material as defined
above, in a solvent system to form an inner coated core; coating
the inner coated core with an outer coating preparation comprising
a pH dependently soluble (or second) polymeric material which has a
pH threshold of about pH 5 or above in a solvent system, to form an
outer coated core, wherein, where the soluble (or third) polymeric
material is a non-ionic polymer, the inner coating preparation
comprises at least one additive selected from the group consisting
of a buffer agent and a base.
The outer coating layer preparation preferably includes a
digestible (or first) polymeric material and the solvent system of
the inner coating preparation is preferably aqueous.
In embodiments where the third polymeric material is an at least
partially neutralised polycarboxylic acid polymer, said method
typically comprises dispersing a polycarboxylic acid polymer in a
solvent, optionally with a buffer agent, and adding base to at
least partially neutralise the polycarboxylic acid polymer to form
the inner coating preparation. In preferred embodiments, the amount
of base added is at least sufficient to fully neutralise the
polycarboxylic acid polymer.
In embodiments where the third polymeric material is a non-ionic
polymer, the pH of the inner coating preparation is preferably
adjusted prior to coating to be at least 0.5 pH units higher than
the pH threshold of the second polymeric material.
The pH of the inner coating preparation is preferably adjusted to
be from about pH 5.5 to about pH 10, e.g. from about pH 7.5 to
about pH 8.5, preferably from about pH 7.8 to about pH 8.2, and
more preferably about pH 8.
The outer coating may be applied using the method described in
WO2007/122374A.
EXAMPLES
Preferred embodiments of the present invention will now be
described with reference to the drawings, in which:--
FIG. 1 is a graph comparing drug release in 0.1N HCl (2 hours)
followed by Krebs buffer pH 7.4 as a function of time, from 400 mg
5ASA tablets, coated with (a) an isolation layer of HPMC, an inner
layer of neutralized Eudragit S and an outer layer of Eudragit.RTM.
S (Example 1), (b) coated with an inner layer of neutralized
Eudragit S and an outer layer of Eudragit.RTM. S (Comparative
Example 1) and (c) coated with a single layer of Eudragit S
(Comparative Example 2);
FIG. 2 is a graph comparing drug release in 0.1N HCl (2 h) followed
by Krebs buffer pH 7.4 as a function of time from 400 mg 5ASA
tablets coated with an isolation layer of HPMC, an inner layer of
neutralized Eudragit.RTM. S and an outer layer of Eudragit.RTM. S
(Example 1) after storage at 40.degree. C./75% RH for (a) 0 days,
(b) 15 days and (c) 45 days;
FIG. 3 is a graph comparing drug release in 0.1N HCl (2 h) followed
by Krebs buffer pH 7.4 as a function of time from 400 mg 5ASA
tablets coated with an inner layer of neutralized Eudragit.RTM. S
and an outer layer of Eudragit.RTM. S (Comparative Example 1) after
storage at 40.degree. C./75% RH for (a) 0 days, (b) 15 days and (c)
45 days;
FIG. 4 is a graph comparing drug release in 0.1N HCl (2 h) followed
by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA
tablets coated with (a) an isolation layer of HPMC, an inner layer
of neutralized Eudragit.RTM. S and an outer layer of 30:70 mixture
of starch:Eudragit.RTM. S (Example 2), (b) an isolation layer of
PVA (Opadry AMB), an inner layer of neutralized Eudragit.RTM. S and
an outer layer of 30:70 mixture of starch:Eudragit.RTM. S (Example
3), (c) an inner layer of neutralized Eudragit.RTM. S and an outer
layer of 30:70 mixture of starch:Eudragit.RTM. S (Comparative
Example 3), (d) an isolation layer of HPMC and an outer layer of
30:70 mixture of starch:Eudragit.RTM. S (Comparative Example 4),
(e) an outer layer of 30:70 mixture of starch:Eudragit.RTM. S
(Comparative Example 5);
FIG. 5 is a graph comparing drug release in 0.1N HCl (2 h) followed
by Krebs buffer pH 7.4 as a function of time from 1200 mg 5ASA
tablets coated with an isolation layer of HPMC, an inner layer of
neutralized Eudragit.RTM. S and an outer layer of 30:70 mixture of
starch:Eudragit.RTM. S, wherein the isolation layer has a thickness
of (a) 1 mg/cm.sup.2 (Comparative Example 6) (b) 3 mg/cm.sup.2
(Example 4), or (c) 5 mg/cm.sup.2 (Comparative Example 7);
FIG. 6 is a graph comparing drug release in 0.1N HCl (2 h) followed
by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA
tablets coated with an inner layer of neutralized Eudragit.RTM. S
and an outer layer of 30:70 mixture of starch:Eudragit.RTM. S
(Comparative Example 3) before storage (Initial) and after storage
in a closed HDPE bottle at 40.degree. C./75% RH for 1 month and 3
months;
FIG. 7 is a graph comparing drug release in 0.1N HCl (2 h) followed
by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA
tablets coated with an isolation layer of HPMC, an inner layer of
neutralized Eudragit.RTM. S and an outer layer of 30:70 mixture of
starch:Eudragit.RTM. S (Example 2) before storage (Initial) and
after storage in a closed HDPE bottle at 40.degree. C./75% RH for 1
month and 3 months;
FIG. 8 is a graph comparing drug release in 0.1N HCl (2 h) followed
by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA
tablets coated with an isolation layer of HPMC, an inner layer of
neutralized Eudragit.RTM. S and an outer layer of 50:50 mixture of
starch:Eudragit.RTM. S (Example 5) before storage (Initial) and
after storage in a closed HDPE bottle at 40.degree. C./75% RH for 1
month and 3 months;
FIG. 9 is a graph depicting drug release in 0.1N HCl (2 h) followed
by Krebs buffer pH 7.4 as a function of time from 800 mg 5ASA
tablets coated with an inner layer of neutralized Eudragit.RTM. S
and an outer layer of 30:70 mixture of starch:Eudragit.RTM. S
(Comparative Example 3) before storage (Initial) and after storage
in an open HDPE bottle at 25.degree. C./60% RH for 1 month and for
3 months;
FIG. 10 is a graph depicting drug release in 0.1N HCl (2 h)
followed by Krebs buffer pH 7.4 as a function of time from 800 mg
5ASA tablets coated with an isolation layer of HPMC, an inner layer
of neutralized Eudragit.RTM. S and an outer layer of 30:70 mixture
of starch:Eudragit.RTM. S (Example 2) before storage (Initial) and
after storage in an open HDPE bottle at 25.degree. C./60% RH for 1
month and 3 months;
FIG. 11 is a graph comparing drug release in 0.1N HCl (2 h)
followed by Krebs buffer pH 7.4 as a function of time from 800 mg
5ASA tablets coated with an isolation layer of HPMC, an inner layer
of neutralized Eudragit.RTM. S and an outer layer of 50:50 mixture
of starch:Eudragit.RTM. S (Example 5) before storage (Initial) and
after storage in an open HDPE bottle at 25.degree. C./60% RH for 1
month and 3 months.
MATERIALS
5-aminosalicylic acid (mesalazine EP) was purchased from Cambrex
Karlskoga AB, Karlskoga, Sweden. Lactose (Tablettose 80) was
purchased from Meggle, Hamburg, Germany. Sodium starch glycolate
(Explotab.TM.) was purchased from JRS Pharma, Rosenberg, Germany.
Talc was purchased from Luzenac Deutschland GmbH, Dusseldorf,
Germany. Polyvinylpyrrolidone (PVP) was purchased from ISP Global
Technologies, Koln, Germany. Magnesium stearate was purchased from
Peter Greven GmbH, Bad Munstereifel, Germany. Eudragit.RTM. S 100,
Eudragit.RTM. L 30 D-55 and Eudragit.RTM. FS 30 D were all
purchased from Evonik GmbH, Darmstadt, Germany. Maize starch
(NI-460 and Eurylon VI or 6) was purchased from Roquette, Lestrem,
France. Polysorbate 80, butan-1-ol and sodium hydroxide were all
purchased from Sigma-Aldrich, Buchs, Switzerland. Potassium
dihydrogen phosphate, glyceryl monostearate (GMS), triethyl citrate
(TEC) and ammonia solution (25%) were all purchased from VWR
International LTD, Poole, UK.
Preparation of 400 mg 5ASA Tablet Cores
Oblong shaped 400 mg 5ASA tablet cores with dimensions
14.5.times.5.7 mm were prepared by fluid bed granulation followed
by blending and compression. Each tablet contained 76.9 wt % 5ASA
(400 mg; drug); 14.7 wt % lactose (filler); 1.7 wt % PVP (binder);
3.5 wt % sodium starch glycolate (disintegrant); and 2 wt % talc
and 1.2 wt %) magnesium stearate (lubricants).
The obtained tablet cores were coated as discussed below in
Examples 1 & 2 and in Comparative Examples 1 to 5.
Preparation of 800 mg 5ASA Tablet Cores
Oblong shaped 800 mg tablets with dimensions 8.times.17 mm were
prepared by granulation followed by blending and compression. Each
tablet contained 800 mg 5ASA (drug) and additional excipients,
including lactose (filler); PVP (binder); sodium starch glycolate
(disintegrant); and talc and magnesium stearate (lubricants).
The obtained tablet cores were coated as discussed below in
Examples 8 to 11 and in Comparative Examples 7 to 11.
Preparation of 1200 mg 5ASA Tablet Cores
Oblong-shaped 1200 mg 5ASA tablet cores (having dimensions
21.times.10 mm) were prepared by wet granulation. Each tablet
contained 85.7 wt % 5ASA (1200 mg), 9.2 wt % microcrystalline
cellulose, 1.7 wt % HPMC, 2.9 wt % sodium starch glycolate, and 0.5
wt % magnesium stearate.
The obtained tablet cores were coated as discussed below in
Examples 3 to 7 and in Comparative Example 6.
Example 1 (400 mg 5ASA Tablets with Isolation Layer of HPMC/Inner
Layer of Neutralised Eudragit.RTM. S/Outer Layer of Eudragit.RTM.
S)
Isolation Layer
The isolation layer was formed from a mixture of HPMC and 10%
triethyl citrate (TEC), based on dry polymer weight.
The HPMC was dissolved in water under magnetic stirring and then
TEC was added to form a coating preparation. The coating
preparation was sprayed onto 400 mg 5ASA cores using a fluid bed
spray coating machine to achieve a coating amount of 3 mg
polymer/cm.sup.2.
The coating parameters were as follows: spray rate 3.1 g/min/kg
tablet cores, atomizing pressure 0.2 bar, and inlet air temperature
40.degree. C.
Inner Layer
The inner layer was applied to the isolation layer coated tablets
from an aqueous preparation of Eudragit.RTM. S 100, where the pH
was adjusted to pH 8. The composition of the inner layer also
included 50% of triethyl citrate (based on dry polymer weight), 10%
potassium dihydrogen phosphate (based on dry polymer weight), 10%
glyceryl monostearate (based on dry polymer weight) and 40%
polysorbate 80 (based on GMS weight). The pH was adjusted using 1M
NaOH until the pH 8 was obtained.
Potassium dihydrogen phosphate and triethyl citrate were dissolved
in distilled water, after which a dispersion of Eudragit.RTM. S 100
was added under mechanical agitation. The pH was then adjusted to
pH 8 with 1M NaOH and the solution was left mixing for 1 hour.
A GMS emulsion was prepared at a concentration of 10% w/w.
Polysorbate 80 (40% based on GMS weight) was dissolved in distilled
water followed by dispersion of GMS. This preparation was then
heated to 75.degree. C. for 15 minutes under strong magnetic
stirring in order to form the emulsion. The emulsion was cooled to
room temperature under stirring.
The GMS emulsion was added to the neutralised Eudragit.RTM. S
solution to form an inner layer coating preparation which was
coated onto the isolation layer coated tablets using a fluid bed
spray coating machine until the coating amount reached 5 mg
polymer/cm.sup.2 to form inner layer coated tablets.
The coating parameters were as follows: spraying rate 20 ml/min/kg
tablets, atomizing pressure 0.2 bar and inlet air temperature
40.degree. C.
Outer Layer
The outer coating layer was applied from an organic solution of
Eudragit.RTM. S 100. The coating solution contains 20% triethyl
citrate (based on dry polymer weight), 10% glyceryl monostearate
(based on dry polymer weight) and 40% polysorbate 80 (based on GMS
weight).
Triethyl citrate was dissolved in 96% ethanol followed by
Eudragit.RTM. S 100 under mechanical stirring and mixing was
continued for 1 hour.
A GMS emulsion was prepared at a concentration of 10% w/w.
Polysorbate 80 (40% based on GMS weight) was dissolved in distilled
water followed by dispersion of the GMS. This dispersion was then
heated to 75.degree. C. for 15 minutes under strong magnetic
stirring in order to form the emulsion. The emulsion was cooled to
room temperature under stirring.
The GMS preparation was added to the Eudragit.RTM. S 100 solution
and the final coating solution was coated on to the inner layer
coated tablets using a fluid bed spray coating machine to achieve a
coating amount of 5 mg Eudragit.RTM. S polymer/cm.sup.2.
The coating parameters were as follows: spraying rate 16 ml/min/kg
tablets, atomizing pressure 0.2 bar and inlet air temperature
40.degree. C.
Example 2 (800 mg 5ASA Tablets with Isolation Layer of HPMC/Inner
Layer of Neutralised Eudragit.RTM. S/Outer Layer of 30:70 Mixture
of Starch:Eudragit.RTM. S)
Isolation Layer
The isolation layer was formed from a mixture of HPMC and 20% PEG
6000 (based on dry polymer weight).
The polymer was dissolved in water under magnetic stirring and then
the PEG 6000 was added. The final preparation was sprayed onto 800
mg 5ASA cores using a perforated pan coater to achieve a coating
amount of 3 mg polymer/cm.sup.2 to form isolation layer coated
tablets. The coating parameters were as follows: spray rate 2.4
g/min/kg tablet cores, atomizing pressure 0.7 bar, and inlet air
volume 15 m.sup.3/h/Kg tablets and product temperature 34.degree.
C.
Inner Layer
The inner layer was applied using an aqueous preparation of
Eudragit.RTM. S 100, where the pH was adjusted to pH 8. The
composition of the middle layer also includes 70% triethyl citrate
(based on dry polymer weight), 1% potassium dihydrogen phosphate
(based on dry polymer weight), 10% glyceryl monostearate (based on
dry polymer weight) and 40% polysorbate 80 (based on GMS weight).
The pH was adjusted using 1M NaOH until the pH 8 is obtained.
Potassium dihydrogen phosphate and triethyl citrate were dissolved
in distilled water, followed by dispersion of the Eudragit.RTM. S
100 under mechanical agitation. The pH was then adjusted to pH 8
with 1M NaOH and left mixing for 1 h.
A GMS emulsion was prepared at a concentration of 10% w/w.
Polysorbate 80 (40% based on GMS weight) was dissolved in distilled
water followed by dispersion of GMS. This preparation was then
heated to 75.degree. C. for 15 minutes under strong magnetic
stirring in order to form an emulsion. The emulsion was cooled to
room temperature under stirring.
The GMS emulsion was added to the neutralised Eudragit.RTM. S
solution and the final preparation was coated onto isolation layer
coated tablets using a perforated pan coater until the coating
amount reached 5 mg polymer/cm.sup.2 to produce inner layer coated
tablets. The total solids content of the coating solution was 10%.
The coating parameters were as follows: spraying rate 3.1 g/min/kg
tablets, atomizing pressure 0.6 bar, inlet air volume 15 m3/h/Kg
tablets and product temperature 26.5.degree. C.
Outer Layer
The outer layer was applied using a mixture of an aqueous starch
dispersion and an organic Eudragit.RTM. S 100 solution. The aqueous
starch dispersion was prepared by dispersing maize starch into
butan-1-ol, followed by water, under magnetic stirring. The ratio
of maize starch:butan-1-ol:water was 1:2:22. The resulting
dispersion was heated to boiling and then cooled under stirring
overnight. The organic Eudragit.RTM. S 100 solution was prepared by
dissolving Eudragit.RTM. S 100 in 96% ethanol under high speed
stirring. The final solution contained about 6% polymer solids.
The starch dispersion was added dropwise to the Eudragit.RTM. S 100
solution to obtain a ratio of starch:Eudragit.RTM. S of 30:70. The
mixture was mixed for 2 h, 20% triethyl citrate (based on total
polymer weight) and 5% glyceryl monostearate (GMS, based on total
polymer weight) were added and mixing was continued for a further 2
h.
13.18% iron oxide red (based on Eudragit.RTM. polymer weight) and
2.27% iron oxide yellow (based on Eudragit.RTM. polymer weight)
were suspended in ethanol under high shear homogenization and this
suspension was added into the starch and Eudragit.RTM. mixture and
mixed for a further 30 minutes.
The GMS was added in the form of an emulsion prepared at a
concentration of 5% w/w. Polysorbate 80 (40% based on GMS weight)
was dissolved in distilled water followed by dispersion of the GMS.
This dispersion was then heated to 75.degree. C. for 15 minutes
under strong magnetic stirring in order to form an emulsion. The
emulsion was cooled to room temperature under stirring.
The final preparation was coated onto the inner layer coated
tablets using a perforated pan coater machine until a coating
having 5 mg Eudragit.RTM. polymer/cm.sup.2 was obtained. The spray
coating parameters were as follows: spraying rate 8.0 g/min/kg
tablets, atomizing pressure 0.4 bar, inlet air volume 100
m.sup.3/h/Kg tablets and product temperature 34.5.degree. C.
Example 3 (800 mg 5ASA Tablets with Isolation Layer of PVA/Inner
Layer of Neutralised Eudragit.RTM. S/Outer Layer of a 30:70 Mixture
of Starch/Eudragit.RTM. S)
Isolation Layer
The isolation layer was formed using Opadry.RTM. AMB (a polyvinyl
alcohol-based product).
The polymer was dissolved in water under magnetic stirring and
mixed for 45 minutes. The final preparation was sprayed onto 800 mg
5ASA cores using a pan-coating machine to achieve a coating amount
of 3.61 mg Opadry.RTM./cm.sup.2. The coating parameters were as
follows: spray rate 7.0 g/min/kg tablet cores, atomizing pressure
0.6 bar, inlet air volume 75 m.sup.3/h per kg tablet cores and
product temperature 42.degree. C.
Inner Layer
The inner layer was prepared according to Example 2.
Outer Layer
The outer layer was prepared according to Example 2
Example 4 (1200 mg 5ASA Tablets with Isolation Layer of HPMC (3
mg/cm.sup.2)/Inner Layer of Neutralised Eudragit.RTM. S/Outer Layer
of 30:70 Mixture of Starch:Eudragit.RTM. S)
Isolation Layer
The isolation layer was prepared according to Example 2. The final
preparation was sprayed onto 1200 mg 5ASA cores using a perforated
pan-coating machine to achieve a coating amount of 3 mg
polymer/cm.sup.2 to form isolation layer coated tablets. The
coating parameters were as follows: spray rate 2.33 g/min. per kg
tablet cores, atomizing pressure 0.7 bar, inlet air volume 16.3
m.sup.3/h per kg tablet cores and product temperature 33.degree.
C.
Inner Layer
The inner coating was prepared according to Example 2. The final
preparation was coated on to the isolation layer coated tablets
using a perforated pan coater machine until the coating amount
reached 5 mg polymer/cm.sup.2. The total solids content of the
coating solution is approximately 10%.
The coating parameters were as follows: spraying rate 2.9 g/min/kg
tablets, atomizing pressure 0.6 bar, and inlet air volume 16.3
m.sup.3/h/kg tablets and product temperature 33.degree. C.
Outer Layer
The outer layer was prepared according to Example 2. The final
preparation was coated onto inner layer coated tablets using a
perforated pan coater machine until a coating having 5 mg
Eudragit.RTM. S polymer/cm.sup.2 was obtained. The spray coating
parameters were as follows: spraying rate 3.1 g/min/kg tablets,
atomizing pressure 0.4 bar, inlet air volume 21.7 m.sup.3/h/kg
tablets and product temperature 34.degree. C.
Example 5 (800 mg 5ASA Tablets with Isolation Layer of HPMC/Inner
Layer of Neutralised Eudragit.RTM. S/Outer Layer of a 50:50 Mixture
of Starch/Eudragit.RTM. S)
Isolation Layer
The isolation layer was prepared according to Example 2.
Inner Layer
The inner layer was prepared according to Example 2
Outer Layer
The outer layer was applied from a mixture of an aqueous starch
dispersion and an organic Eudragit.RTM. S 100 solution.
The aqueous starch dispersion was prepared by dispersing maize
starch into butan-1-ol, followed by water, under magnetic stirring.
The ratio of maize starch:butan-1-ol:water was 1:1:9.53. The
resulting dispersion was heated to boiling and then cooled under
stirring overnight. The % solids content of the cooled preparation
was calculated based on the final weight of the dispersion
(considering the evaporation during heating).
The organic Eudragit.RTM. S 100 solution was prepared by dissolving
Eudragit.RTM. S 100 in 96% ethanol under high speed stirring. The
final solution contained about 6% polymer solids.
The starch dispersion was added dropwise to the Eudragit.RTM. S 100
solution to obtain a ratio of starch:Eudragit.RTM. S of 50:50. The
mixture was mixed for 2 h, 20% triethyl citrate (based on total
polymer weight) and 5% glyceryl monostearate (GMS, based on total
polymer weight) were added and mixing continued for a further 2
h.
13.18% iron oxide red (based on Eudragit.RTM. polymer weight) and
2.27% iron oxide yellow (based on Eudragit.RTM. polymer weight)
were suspended in ethanol under high shear homogenization and this
suspension was added into the starch and Eudragit mixture and
mixing continued for a further 30 minutes.
The GMS was added in the form of an emulsion prepared at a
concentration of 5% w/w. Polysorbate 80 (40% based on GMS weight)
was dissolved in distilled water followed by dispersion of the GMS.
This dispersion was then heated to 75.degree. C. for 15 minutes
under strong magnetic stirring in order to form an emulsion. The
emulsion was cooled to room temperature under stirring. The final
preparation was coated onto the inner layer coated tablets using a
perforated pan coater until a coating having 5 mg Eudragit.RTM. S
polymer/cm.sup.2 was obtained. The spray coating parameters were as
follows: spraying rate 8.0 g/min/kg tablets, atomizing pressure 0.4
bar, inlet air volume 100 m.sup.3/h/kg tablets and product
temperature 35.5.degree. C.
Comparative Example 1 (400 mg 5ASA Tablets with Inner Layer of
Neutralised Eudragit.RTM. S/Outer Layer of Eudragit.RTM. S)
Inner Layer
The inner layer was prepared according to Example 1.
Outer Layer
The outer layer was prepared according to Example 1
Comparative Example 2 (400 mg 5ASA Tablets with a Single Layer of
Eudragit.RTM. S)
The single layer of Eudragit S was prepared according to Example 1
and applied directly on 400 mg 5ASA tablet cores (without isolation
and without inner layer).
Comparative Example 3 (800 mg 5ASA Tablets with Inner Layer of
Neutralised Eudragit.RTM. S/Outer Layer of a 30:70 Mixture of
Starch:Eudragit.RTM. S)
Inner Layer
The inner layer was prepared according to Example 2.
Outer Layer
The outer layer was prepared according to Example 2.
Comparative Example 4 (800 mg 5ASA Tablets with Isolation Layer of
HPMC/Outer Layer of a 30:70 Mixture of Starch:Eudragit.RTM. S)
Isolation Layer
The isolation layer was prepared according to Example 2
Outer Layer
The outer layer was prepared according to Example 2
Comparative Example 5 (800 mg 5ASA Tablets with a Single Layer of a
30:70 Mixture of Starch/Eudragit.RTM. S)
The single layer of a 30:70 mixture of starch/Eudragit.RTM. S was
prepared according to Example 2, and applied directly on 800 mg
5ASA tablet cores (without isolation layer and without inner
layer).
Comparative Example 6 (1200 mg 5ASA Tablets with Isolation Layer of
HPMC (1 Mg/Cm.sup.2)/Inner Layer of Neutralised Eudragit.RTM.
S/Outer Layer of 30:70 Mixture of Starch:Eudragit.RTM. S)
Isolation Layer
The isolation layer was applied from a mixture of HPMC and 20%
polyethylene glycol 6000 (PEG 6000), based on dry polymer
weight.
The HPMC polymer was dissolved in water under magnetic stirring and
then PEG 6000 was added. The final preparation was sprayed onto
1200 mg 5-ASA cores using a perforated pan-coating machine to
achieve a coating amount of 1 mg polymer/cm.sup.2 to form isolation
layer coated tablets.
The coating parameters were as follows: spray rate 9.75 g/min. per
kg tablet cores, atomizing pressure 0.7 bar, inlet air volume 75
m.sup.3/h/kg tablets and product temperature 32.degree. C.
Inner Layer
The inner layer was prepared according to Example 4
Outer Layer
The outer layer was prepared according to Example 4.
Comparative Example 7 (1200 mg 5ASA Tablets with Isolation Layer of
HPMC (5 Mg/Cm.sup.2)/Inner Layer of Neutralised Eudragit.RTM.
S/Outer Layer of 30:70 Mixture of Starch:Eudragit.RTM. S)
Isolation Layer
The isolation layer was formed from a mixture of HPMC and 20%
polyethylene glycol 6000 (PEG 6000), based on dry polymer
weight.
The HPMC polymer was dissolved in water under magnetic stirring and
then PEG 6000 was added. The final preparation was sprayed onto
1200 mg 5ASA cores using a pan-coating machine to achieve a coating
amount of 5 mg polymer/cm.sup.2 to form isolation layer coated
tablets.
Inner Layer
The inner layer was prepared according to Example 4.
Outer Layer
The outer layer was prepared according to Example 4.
The coating parameters were as follows: spray rate 5.75 g/min. per
kg tablet cores, atomizing pressure 0.7 bar, inlet air volume 75
m.sup.3/h per kg tablet cores and product temperature 32.degree.
C.
Drug Release Test--Effect of pH Alone
In vitro dissolution studies were performed on a USP type II
apparatus using a paddle speed of 50 rpm and a media temperature of
37.+-.0.5.degree. C. Tablets were first tested in 0.1 M HCl for 2 h
followed by 8 h in Krebs buffer (pH 7.4). The pH of the buffer was
stabilized at 7.4.+-.0.05 by continuously sparring with 5%
CO.sub.2/95% O.sub.2. Absorbance measurements were taken at 5
minute intervals, with an absorbance wavelength of 301 nm in HCl
and 330 nm in Krebs buffer. The composition per liter of Krebs
buffer is 0.16 g of KH.sub.2PO.sub.4, 6.9 g of NaCl, 0.35 g KCl,
0.29 g MgSO.sub.4.7H.sub.2O, 0.376 g CaCl.sub.2.2H.sub.2O and 2.1 g
NaHCO.sub.3. Only the measurements taken at 30 or 60 minute
intervals are depicted in the figures.
Storage
Drug release was tested before storage (Initial) and after storage
under different conditions at the 1 month and 3 month points. The
storage conditions exemplified herein are (i) open HDPE bottles at
25.degree. C./60% RH (relative humidity); (ii) closed HDPE bottles
at 25.degree. C./60% RH; (iii) open HDPE bottle at 40.degree.
C./75% RH; and (iv) closed HDPE bottles 40.degree. C./75% RH.
Results
The results depicted in FIG. 1 clearly indicate that initial drug
release is quicker (i.e. T.sub.lag is reduced) from 400 mg 5ASA
tablets coated with an isolation layer of HPMC, an inner layer of
neutralized Eudragit S and an outer layer of Eudragit S (Example 1)
than if the isolation layer is absent (Comparative Example 1) or
both the isolation layer and the inner layer are absent
(Comparative Example 2).
The results depicted in FIGS. 2 to 3 indicate that the drug release
is substantially unaffected after storage (at 40.degree. C./75% RH)
after 45 days from tablets coated with an HPMC isolation layer, an
inner layer of neutralized Eudragit S and outer layer of Eudragit S
(Example 1) when compared to equivalent tablets without the
isolation layer (Comparative Example 1). Clearly, the use of an
HPMC isolation layer improves the stability of the tablets during
storage.
The results depicted in FIG. 5 indicate that initial release drug
release is quicker from 1200 mg 5ASA tablets coated with an
isolation layer of HPMC, an inner layer of neutralized Eudragit S
and an outer layer of a 30:70 mixture of starch:Eudragit S when the
isolation layer has a thickness of 3 mg polymer/cm.sup.2 (Example
4) than if the isolation layer has a thickness of 1 mg
polymer/cm.sup.2 (Comparative Example 6) or 5 mg polymer/cm.sup.2
(Comparative Example 7)) although it should be noted that initial
release is accelerated in each of these cases.
Turning to FIGS. 4 to 11, the results indicate that presence of an
isolation layer made of HPMC (Example 2) leads to a faster drug
release compared to tablets coated only with an inner layer of
neutralized Eudragit S and an outer layer of a 30:70 mixture of
starch:Eudragit S (Comparative Example 3). Furthermore, in the
absence of the middle layer (Comparative Example 4), the isolation
layer contributes to a later drug release when compared to a single
layer of 30:70 mixture of starch:Eudragit S (Comparative Example
5). This result demonstrates that improved drug release is not
inevitable if an isolation layer is present between the core and
the alkaline inner layer.
Moreover, when using an isolation layer of PVA, the contribution to
drug release acceleration was actually higher than the one given by
the inner layer alone (Example 3, Comparative Example 3 and
Comparative Example 9). In the absence of isolation layer
(Comparative Example 3), after 1 month storage at 40.degree. C./75%
RH, the drug release was delayed even if stored in closed HDPE
bottles. However, the presence of an HPMC isolation layer (Example
2) avoided the delay in drug release after 1 month at 40.degree.
C./75% RH for the tablets stored in closed HDPE bottles. The same
observations are also valid when the outer layer has a 50:50
mixture of starch and Eudragit S (Example 5).
At 25.degree. C./60% RH, even in open conditions, there is no
significant change in drug release if an isolation layer is present
(Example 2 and Example 5), whereas in the absence of the isolation
layer (Comparative Example 3), tablets stored openly show a delayed
release after 1 month.
It can be seen therefore that the delayed release formulation
according to the present invention is significantly superior to
comparative formulations.
Whilst the invention has been described with reference to a
preferred embodiment, it will be appreciated that various
modifications are possible within the spirit or scope of the
invention as defined in the following claims.
In this specification, unless expressly otherwise indicated, the
word `or` is used in the sense of an operator that returns a true
value when either or both of the stated conditions is met, as
opposed to the operator `exclusive or` which requires that only one
of the conditions is met. The word `comprising` is used in the
sense of `including` rather than in to mean `consisting of`. All
prior teachings acknowledged above are hereby incorporated by
reference. No acknowledgement of any prior published document
herein should be taken to be an admission or representation that
the teaching thereof was common general knowledge in Australia or
elsewhere at the date hereof.
* * * * *